JP2022043060A - Combination therapies - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a combination formulation for use in treating cancer in subjects comprising an immunomodulator and a second therapeutic agent.

SOLUTION: In a combination formulation, (i) the immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof, where the inhibitor of immune checkpoint molecule is selected from inhibitors of PD-1, PD-L1 etc., the activator of co-stimulatory molecule is selected from agonists of, for example, OX40, CD2, and CD27; and ii) the second therapeutic agent is selected from one or more of: 1) an IAP inhibitor; 2) a Tor kinase inhibitor; 3) a HDM2 ligase inhibitor; 4) a PIM kinase inhibitor; 5) a HER3 kinase inhibitor; 6) a histone deacetylase (HDAC) inhibitor; 7) a Janus kinase inhibitor; and 8) a FGF receptor inhibitor.

SELECTED DRAWING: Figure 7A

COPYRIGHT: (C)2022,JPO&INPIT

Description

Cross-reference to related applications This application claims priority under US Provisional Application No. 62 / 059,832 filed on October 3, 2014, and the content of the application is incorporated herein by reference in its entirety. Including.

Sequence Listing This application is provided electronically in ASCII format and includes a sequence listing, which is hereby incorporated by reference in its entirety. The ASCII copy was created on October 1, 2015, is named C2160-7006WO_SL.txt, and has a size of 14,618 bytes.

Background The ability of T cells to mediate an immune response to an antigen requires two different signaling interactions (Viglietta, V. et al. (2007) Neurotherapeutics 4: 666-675; Korman, AJ et al. ( 2007) Adv. Immunol. 90: 297-339). First, antigens aligned on the surface of antigen-presenting cells (APCs) are presented to antigen-specific naive CD4 ⁺ T cells. Such presentation delivers the signal via the T cell receptor (TCR), which directs T cells to initiate an immune response specific for the presented antigen. Second, various costimulatory and inhibitory signals mediated by interactions between T cell surface molecules that differ from APCs induce T cell activation and proliferation and ultimately its inhibition. ..

The immune system is tightly regulated by a network of co-stimulatory and co-inhibiting ligands and receptors. These molecules provide a second signal of T cell activation, providing a balanced network of positive and negative signals to maximize the immune response to infection and at the same time limit immunity to self ( Wang, L. et al. (Epub Mar. 7, 2011) J. Exp. Med. 208 (3): 577-92; Lepenies, B. et al. (2008) Endocrine, Metabolic & Immune Disorders--Drug Targets 8: 279-288). Examples of co-stimulatory signals include the binding of APC's B7.1 (CD80) and B7.2 (CD86) ligands to the CD28 and CTLA-4 receptors of CD4 ⁺ T lymphocytes (Sharpe, AH et al. (Sharpe, AH et al. 2002) Nature Rev. Immunol. 2: 116-126; Lindley, PS et al. (2009) Immunol. Rev. 229: 307-321). Binding of B7.1 or B7.2 to CD28 stimulates T cell activation, whereas binding of B7.1 or B7.2 to CTLA-4 inhibits such activation (Dong, C.I. et al. (2003) Immunolog. Res. 28 (1): 39-48; Greenwald, RJ et al. (2005) Ann. Rev. Immunol. 23: 515-548). CD28 is constitutively expressed on the surface of T cells (Gross, J., et al. (1992) J. Immunol. 149: 380-388), while CTLA-4 expression rises rapidly after T cell activation. Controlled (Linsley, P. et al. (1996) Immunity 4: 535-543).

Other ligands for the CD28 receptor include a group of related B7 molecules, also known as the "B7 superfamily" (Coyle, A. J. et al. (2001) Nature Immunol. 2 (3): 203-209; Sharpe, A. H. et al. (2002) Nature Rev. Immunol. 2: 116-126; Collins, M. et al. (2005) Genome Biol. 6: 223.1-223.7; Korman, A. J. et al. (2007) Adv. Immunol. 90 : 297-339). Several members of the B7 superfamily are known, B7.1 (CD80), B7.2 (CD86), inducible co-stimulatory molecular ligand (ICOS-L), programmed death-1 ligand (PD-L1; B7-). H1), Programmed Death-2 Ligand (PD-L2; B7-DC), B7-H3, B7-H4 and B7-H6 (Collins, M. et al. (2005) Genome Biol. 6: 223.1-223.7) ).

Programmed death 1 (PD-1) protein is an inhibitory member of the extended CD28 / CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. ( 2003) J. Immunol. 170: 711-8). Other members of the CD28 family include CD28, CTLA-4, ICOS and BTLA. It is suggested that PD-1 exists as a monomer lacking the unpaired cysteine characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells and monocytes.

PD-1 encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8: 765-72). Structurally similar to CTLA-4, PD-1 lacks the MYPPY motif (SEQ ID NO: 1) important for B7-1 and B7-2 binding. Two ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been identified, which downregulate T cell activation by binding to PD-1. It has been shown (Freeman et al. (2000) J. Exp. Med. 192: 1027-34; Carter et al. (2002) Eur. J. Immunol. 32: 634-43). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1 but not to other CD28 family members. PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8: 787-9).

PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals (Ishida, Y. et al. (1992) EMBO J. 11: 3887-3895; Blank, C. et al. (Epub 2006 Dec). . 29) Immunol. Immunother. 56 (5): 739-745). The interaction of PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, for example, tumor infiltrating lymphocyte depletion, T cell receptor-mediated proliferation reduction and / or immune avoidance by cancerous cells. (Dong et al. (2003) J. Mol. Med. 81: 281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54: 307-314; Konishi et al. (2004) Clin. Cancer Res. 10: 5094-100). Immunosuppression can be reversed by blocking the local interaction between PD-1 and PD-L1 or PD-L2; this effect is additive when the interaction between PD-1 and PD-L2 is similarly blocked. (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99: 12293-7; Brown et al. (2003) J. Immunol. 170: 1257-66).

Given the importance of immune checkpoint pathways in the immune response, there is a need to develop new combination therapies that activate the immune system.

Overview The present invention is at least in part a second treatment selected from one or more of the agents listed in Table 1 for immunomodulators (eg, one or more activators of costimulatory molecules or inhibitors of immune checkpoint molecules). Provided are methods and compositions comprising in combination with agents. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5) or CTLA-4). 1 or more inhibitors) can be combined with a second therapeutic agent selected from one or more of the agents listed in Table 1 (eg, 1) IAP inhibitors; 2) TOR kinase inhibitors; 3) HDM2 ligase inhibitors. 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) Histon deacetylase (HDAC) inhibitor; 7) Janus kinase inhibitor; 8) FGF receptor inhibitor; 9) EGF receptor inhibitor; 10) c-MET inhibitors; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CAR T cells that target CD19). ); 16) MEK inhibitor or 17) BCR-ABL inhibitor 1 or more). The combinations described herein can provide beneficial effects, such as enhanced anti-cancer effects, toxicity reduction and / or side effect reduction, in the treatment of cancer, for example. For example, immunomodulators, second therapeutic agents, or both can be administered at the low doses required to achieve the same therapeutic effect compared to monotherapy. Therefore, we disclose compositions and methods for treating proliferative disorders, including cancer, using the combination therapies.

Thus, in one aspect, the invention relates to a method of treating (eg, blocking, alleviating, ameliorating or preventing) a proliferative condition or disorder (eg, cancer) in a subject. The method is selected from subject to immunomodulatory agent (eg, one or more of a co-stimulatory molecule activator or immune checkpoint molecule inhibitor) and a second therapeutic agent, eg, one or more of the agents listed in Table 1. It involves administering a second therapeutic agent, thereby treating a proliferative condition or disorder (eg, cancer). In some embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule (eg, PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5)). Or an inhibitor of CTLA-4 or any combination thereof). In other embodiments, the second therapeutic agent is selected from one or more listed in Table 1, eg, 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) histon deacetylase (HDAC) inhibitor; 7) yanus kinase inhibitor; 8) FGF receptor inhibitor; 9) EGF receptor inhibitor; 10) c-MET inhibitor; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CAR T cells that target CD19); 16) MEK inhibitors or 17) One or more of BCR-ABL inhibitors. The combination of the immunomodulatory agent and the second agent may be administered together in a single composition, but separately in two or more different compositions, eg, one or more compositions or dosage forms as described herein. It may be administered at. Administration of the immunomodulatory agent and the second agent can be in any order. For example, the immunomodulator may be administered before or after the second agent at the same time.

In another aspect, the invention relates to methods of reducing the activity of proliferative (eg, cancer) cells (eg, proliferation, survival, viability or all of them). The method is selected from cells and immunomodulators (eg, one or more of the activators of costimulatory molecules or inhibitors of immune checkpoint molecules) and second therapeutic agents, eg, one or more of the agents listed in Table 1. It involves contacting a second therapeutic agent, thereby reducing cell activity. In some embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule (eg, PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5)). Or an inhibitor of CTLA-4 or any combination thereof). In other embodiments, the second therapeutic agent is selected from one or more listed in Table 1, eg, 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) histon deacetylase (HDAC) inhibitor; 7) yanus kinase inhibitor; 8) FGF receptor inhibitor; 9) EGF receptor inhibitor; 10) c-MET inhibitor; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CAR T cells that target CD19); 16) MEK inhibitors or 17) One or more of BCR-ABL inhibitors.

In certain embodiments, the methods described herein can be used in vitro. For example, an in vitro hPBMC-based assay can be used to screen for combined immunomodulatory and second therapeutic agents signals, as disclosed, for example, in Wang, C. et al. (2014) Cancer Immunology Research 2: 846-856. .. In certain embodiments, the methods described herein can be performed in vivo, eg, on an animal subject or model, or as part of a therapeutic protocol. Contact of cells with immunomodulators and second agents can be in any order. In some embodiments, the cells are contacted with the immunomodulator at the same time as the second agent, before or after. In certain embodiments, the methods described herein are used to infiltrate tumor lymphocytes (TLI) in vitro or in vivo, eg, as disclosed in Frederick, D.T. et al. (2013) Clinical Cancer Research 19: 1225-31. taking measurement.

In some embodiments, the method is in an animal model with cells and immunomodulators (eg, one or more activators of costimulatory molecules or inhibitors of immune checkpoint molecules) and / or second therapeutic agents, eg, Table 1. Includes contact with a second therapeutic agent selected from one or more of the listed agents. In some embodiments, the animal model has mutations that inhibit or activate the IAP, EGF receptor, cMET, ALK, CDK4 / 6, PI3K, BRAF, FGF receptor, MEK and / or BCR-ABL. In one exemplary embodiment, the animal model is a mouse model transplanted with MC38 mouse colon cancer. In another exemplary embodiment, the animal model is an inactivated p110δ isoform of PI3 kinase (eg, p110δ, as disclosed, for example, in Ali, K., et al., (2014) Nature 510: 407-411. It is a mouse model having ^D910A ).

In certain embodiments, the immune phenotype is determined by one or more measurements of expression, activation, signaling, flow cytometry, mRNA analysis, cytokine levels and / or immunohistochemistry. In some embodiments, the immune phenotype is determined systemically, eg, in PBMCs. In some embodiments, the immune phenotype is determined in situ, eg, in tumor cells. In some embodiments, to determine the immune phenotype, one or more of the following parameters are characterized: checkpoint induction; M2 macrophage levels relative to M1 macrophage levels; regulatory T cell levels relative to effector T cell levels; and / or _{TH2 / H17 cell} levels relative to TH1 cell levels.

In other aspects, the invention is an immunomodulator (eg, one or more of a co-stimulatory molecule activator or an immune checkpoint molecule inhibitor) and a second therapeutic agent, eg, one or more of the agents listed in Table 1. With respect to a composition (eg, one or more compositions, formulations or dose formulations) or pharmaceutical combinations comprising a second therapeutic agent selected from. In some embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule (eg, PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5)). Or an inhibitor of CTLA-4 or any combination thereof). In other embodiments, the second therapeutic agent is selected from one or more listed in Table 1, eg, 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) histon deacetylase (HDAC) inhibitor; 7) yanus kinase inhibitor; 8) FGF receptor inhibitor; 9) EGF receptor inhibitor; 10) c-MET inhibitor; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CAR T cells that target CD19); 16) MEK inhibitors or 17) One or more of BCR-ABL inhibitors. In some embodiments, the composition comprises a pharmaceutically acceptable carrier. The immunomodulatory agent and the second agent can be used in a single composition or as two or more different compositions. The immunomodulatory agent and the second agent may be administered by the same route of administration or by different routes of administration. In some embodiments, the pharmaceutical combination comprises an immunomodulatory agent and a second agent separately or together.

In some embodiments, the composition, formulation or pharmaceutical combination is used as a pharmaceutical, eg, for the treatment of a proliferative disorder (eg, cancer as described herein). In some embodiments, the immunomodulatory agent and the second agent are administered simultaneously, eg, independently, simultaneously or at overlapping time intervals or separately at time intervals. In some embodiments, the time interval allows the immunomodulatory agent and the second agent to work together. In some embodiments, the composition, formulation or pharmaceutical combination comprises an amount that is therapeutically effective in combination for the treatment of a proliferative disorder, eg, a cancer as described herein.

In other aspects, the invention is an immunomodulator (eg, one or more of a co-stimulatory molecule activator or an immune checkpoint molecule inhibitor) and the first in the manufacture of a pharmaceutical for the treatment of a proliferative disease, eg, cancer. (Ii) With respect to the use of a composition (eg, one or more compositions, formulations or dose formulations) or pharmaceutical combinations comprising a therapeutic agent, eg, a second therapeutic agent selected from one or more of the agents listed in Table 1. In some embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule (eg, PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5). ) Or CTLA-4 or any combination of these inhibitors). In other embodiments, the second therapeutic agent is selected from one or more listed in Table 1, eg, 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) histon deacetylase (HDAC) inhibitor; 7) yanus kinase inhibitor; 8) FGF receptor inhibitor; 9) EGF receptor inhibitor; 10) c-MET inhibitor; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CAR T cells that target CD19); 16) MEK inhibitors or 17) One or more of BCR-ABL inhibitors.

Select from immunomodulators (eg, one or more of the activators of costimulatory molecules or inhibitors of immune checkpoint molecules as described herein) and second therapeutic agents, eg, one or more of the agents listed in Table 1. Also disclosed are kits containing the second therapeutic agent and instructions for use, such as therapeutic kits.

Further properties or embodiments of the methods, compositions, dosage formulations and kits described herein include one or more of:
In some embodiments, the immunomodulator is an activator of a co-stimulatory molecule. In some embodiments, the agonists of the costimulatory molecule are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40. , BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand or any combination of agonists (eg, agonist antibodies, antigen-binding fragments or soluble fusions thereof). ..

In some embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule. In some embodiments, the immunomodulators are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (eg, CEACAM-1, -3 and / or -5). It is an inhibitor of VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFR beta. In some embodiments, the inhibitor of the immune checkpoint molecule is PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5) or CTLA-4 or Inhibits any combination of these.

Inhibition of inhibitory molecules can be performed at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA or shRNA) can be used to inhibit the expression of the inhibitory molecule. In another embodiment, the inhibitor of the inhibitory signal is a polypeptide, eg, a soluble ligand (eg, PD-1-Ig or CTLA-4 Ig). In other embodiments, the inhibitor of the inhibitory signal is an antibody or antigen-binding fragment thereof that binds to the inhibitory molecule; eg, PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG- 3. An antibody or fragment thereof that binds to CEACAM (eg, CEACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFR beta or a combination thereof (here, "" Also called "antibody molecule").

In some embodiments, the antibody molecule is a complete antibody or fragment thereof (eg, Fab, F (ab') ₂ , Fv or single chain Fv fragment (scFv)). In yet another embodiment, the antibody molecule is selected from the heavy chain constant regions (Fc) of, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE; in particular, eg, for example. , IgG1, IgG2, IgG3 and IgG4, a heavy chain constant region, more specifically an IgG1 or IgG4 heavy chain constant region (eg, human IgG1 or IgG4). In some embodiments, the heavy chain constant region is human IgG1 or human IgG4. In some embodiments, the constant region has been modified, eg, modified to modify the properties of the antibody molecule (eg, Fc receptor binding, antibody glycosylation, cysteine residue count, effector cell function or complement function). To increase or decrease 1 or more).

In some embodiments, the antibody molecule is in the form of a bispecific or multispecific antibody molecule. In some embodiments, the bispecific antibody molecule has first and second binding specificity for PD-1 or PD-L1, eg, second binding specificity for TIM-3, LAG-3 or PD-L2. Has. In some embodiments, the bispecific antibody molecule binds PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1 and CEACAM (eg, CEACAM-1, -3 and / or -5). In another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1 and CEACAM-1. In yet another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1 and CEACAM-3. In yet another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1 and CEACAM-1. In another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1. In yet another embodiment, the bispecific antibody molecule binds PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to TIM-3 and LAG-3. In another embodiment, the bispecific antibody molecule binds to CEACAM (eg, CEACAM-1, -3 and / or -5) and LAG-3. In another embodiment, the bispecific antibody molecule binds to CEACAM (eg, CEACAM-1, -3 and / or -5) and TIM-3. Any combination of said molecules may be applied to a multispecific antibody molecule, eg, a trispecific antibody, which has first binding specificity for PD-1 or PD-1 and TIM-3, CEACAM (eg, CEACAM-). It has second and third binding specificity for one or more of 1, -3 and / or -5), LAG-3 or PD-L2.

In some embodiments, the immunomodulator is an inhibitor of PD-1, eg, human PD-1. In another embodiment, the immunomodulator is an inhibitor of PD-L1, eg, human PD-L1. In some embodiments, the inhibitor of PD-1 or PD-L1 is an antibody molecule against PD-1 or PD-L1. The PD-1 or PD-L1 inhibitor may be used alone or in combination with other immunomodulators, eg, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5) or It can be administered in combination with an inhibitor of CTLA-4. In an exemplary embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a LAG-3 inhibitor, eg, an anti-LAG-3 antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a TIM-3 inhibitor, eg, an anti-TIM-3 antibody molecule. In yet another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 antibody molecule, is combined with a LAG-3 inhibitor, eg, an anti-LAG-3 antibody molecule and a TIM-3 inhibitor, eg, Administer in combination with anti-TIM-3 antibody molecule. In other embodiments, a PD-1 or PD-L1 inhibitor, such as an anti-PD-1 or PD-L1 antibody molecule, is combined with a CEACAM (eg, CEACAM-1, -3 and / or -5) inhibitor, such as. , Administer in combination with anti-CEACAM antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a CEACAM-1 inhibitor, eg, an anti-CEACAM-1 antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a CEACAM-3 inhibitor, eg, an anti-CEACAM-3 antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a CEACAM-5 inhibitor, eg, an anti-CEACAM-5 antibody molecule. Other immunomodulators and PD-1 inhibitors (eg, one or more of PD-L2, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFR) The combination is also within the scope of the present invention. Any of the antibody molecules known in the art or disclosed herein can be used in said combinations of checkpoint molecule inhibitors.

Examples of Immune Checkpoint Molecular Inhibitors In certain embodiments, the PD-1 inhibitor is an anti-PD-1 antibody selected from nivolumab, pembrolizumab or pidirizumab.

In some embodiments, the anti-PD-1 antibody is nivolumab. Other names for nivolumab are MDX-1106, MDX-1106-04, ONO-4538 or BMS-936558. In some embodiments, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1. Other human monoclonal antibodies that specifically bind nivolumab (clone 5C4) and PD-1 are disclosed in US 8,008,449 and WO2006 / 121168.

In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (trade name KEYTRUDA, formerly known as rambrolizumab, Merck 3745, MK-3475 or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab is disclosed, for example, in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, WO2009 / 114335 and US8,354,509.

In some embodiments, the anti-PD-1 antibody is pidirisumab. Pidirisumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD-1. Pidirisumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009 / 101611. Other anti-PD-1 antibodies are disclosed in US8,609,089, US2010028330 and / or US20110114649. Other anti-PD-1 antibodies include AMP 514 (Amplimmune).

In some embodiments, the PD-1 inhibitor is an extracellular or PD-1 binding moiety of PD-Ll or PD-L2 fused to a constant region (eg, the Fc region of an immunoglobulin sequence) of immunoadhesin. Including immunoadhesin). In some embodiments, the PD-1 inhibitor is AMP-224.

In some embodiments, the PD-Ll inhibitor is an anti-PD-Ll antibody. In some embodiments, the anti-PD-Ll inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105.

In some embodiments, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-Ll antibody described in WO2007 / 005874.

In some embodiments, the PD-L1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is the anti-PD-Ll described in WO2010 / 077634 (heavy and light chain variable region sequences set forth in SEQ ID NOs: 20 and 21, respectively of WO2010 / 077634).

In some embodiments, the PD-L1 inhibitor is MDPL3280A (Genentech / Roche). MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds PD-L1. Other human monoclonal antibodies to MDPL3280A and PD-L1 are disclosed in US Pat. No. 7,943,743 and US Publication No. 20120039906.

In another embodiment, the PD-L2 inhibitor is AMP-224. AMP-224 is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD-1 and B7-H1 (B7-DCIg; Amplimmune; eg disclosed in WO2010 / 027827 and WO2011 / 066342).

In some embodiments, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In some embodiments, the LAG-3 inhibitor is BMS-986016, which is described in more detail below.

In some embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule, eg, an anti-TIM-3 antibody molecule as described herein.

The inhibitors of one or more immune checkpoint molecules described above can be used in combination with one or more of the second agents disclosed in Table 1, more specifically exemplified below. In some embodiments, the second agent is selected from one or more of the following:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or 8) 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide.

Examples of Combination Therapy In some embodiments, the inhibitor of PD-1 is disclosed, for example, in US 8,008,449 and has the sequences disclosed herein, eg, the heavy chain sequence of SEQ ID NO: 2 and SEQ ID NO: 3. Nivolumab (CAS Registry No: 946414-94) having a light chain sequence (or a sequence that is substantially identical or similar to it, eg, a sequence that is at least 85%, 90%, 95% or more identical to the particular sequence). -4).

In another embodiment, the inhibitor of PD-1 is disclosed, for example, in US8,354,509 and WO2009 / 114335 and has the sequences disclosed herein, eg, the heavy chain sequence and SEQ ID NO: of SEQ ID NO: 4. Pembrolizumab having a light chain sequence of 5 (or a sequence that is substantially identical or similar to it, eg, a sequence that is at least 85%, 90%, 95% or more identical to the particular sequence).

In another embodiment, the inhibitor of PD-L1 is disclosed, for example, in WO2013 / 0179174 and has the sequences disclosed herein, eg, the heavy chain sequence of SEQ ID NO: 6 and the light chain sequence of SEQ ID NO: 7 (or , MSB0010718C (also referred to as A09-246-2), having a sequence that is substantially identical or similar to it, eg, a sequence that is at least 85%, 90%, 95% or more identical to the particular sequence.

In certain embodiments, PD-1 inhibitors, such as anti-PD-1 antibodies (eg, nivolumab), are used in the methods or compositions described herein. For example, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nibolumab or penbrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other immunomodulatory). In combination with agents), one or more of the agents listed herein, eg, listed in Table 1 or listed in the publications listed in Table 1, eg, 1) inhibitors of apoptosis (IAP) inhibitors; 2) Inhibitors targeting rapamycin (TOR) kinase; 3) Inhibitors of mouse double microchromatoid 2 E3 ubiquitin ligase human homologue (HDM2); 4) PIM kinase inhibitors; 5) Human epithelial cell proliferation factor 3 (HER3) Kinase inhibitor; 6) Histon deacetylase (HDAC) inhibitor; 7) Janus kinase inhibitor; 8) Fibroblast proliferation factor receptor (FGF) receptor inhibitor); 9) Epithelial cell proliferation factor (EGF) ) Receptor inhibitors; 10) c-MET inhibitors; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CD19) Targeted CAR T cells); used in combination with one or more of 16) MEK inhibitors or 17) BCR-ABL inhibitors. In some embodiments, one or more of the above combinations is used to treat a disorder, eg, a disorder described herein (eg, a disorder disclosed in Table 1). In some embodiments, one or more of the above combinations is used to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). Each of these combinations is described in more detail below.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an IAP inhibitor to use a cancer, eg, a cancer described herein (eg, in Table 1). Disclose cancer) to treat. In certain embodiments, IAP inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the IAP inhibitor is LCL161 as disclosed herein or in the literature cited in Table 1. In some embodiments, the IAP inhibitor is disclosed, for example, in US Pat. No. 8,546,336. In some embodiments, the LCL 161 has a structure as disclosed in the publications provided in Table 1 or cited in Table 1. In certain embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, pembrolizumab or one of MSB0010718C) is used in combination with LCL161 to include, eg, the cancers or disorders listed in Table 1, eg, solid tumors. , For example, breast cancer, colon cancer or pancreatic cancer; or hematopoietic tumors, such as multiple myeloma or hematopoietic disorders.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with LCL161, wherein LCL161 is (S) -N-((S) -1-. Cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide.

In certain embodiments, the LCL161 is taken from about 10 to 3000 mg, eg, about 20 to 2400 mg, about 50 to 1800 mg, about 100 to 1500 mg, about 200 to 1200 mg, about 300 to 900 mg, such as about 600 mg, about 900 mg, about 1200 mg. Administer at doses of about 1500 mg, about 1800 mg, about 2100 mg or about 2400 mg (eg, oral doses). In some embodiments, LCL161 is administered once a week or once every two weeks. In some embodiments, LCL161 is administered prior to administration of an immune checkpoint inhibitor (eg, anti-PD-1 antibody). For example, LCL161 may be administered 1 day, 2 days, 3 days, 4 days or 5 days or more before the administration of the anti-PD-1 antibody. In another embodiment, LCL161 is administered simultaneously or substantially simultaneously with the anti-PD-1 antibody (eg, on the same day). In yet another embodiment, LCL161 is administered after administration of an immune checkpoint inhibitor (eg, anti-PD-1 antibody).

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a TOR kinase inhibitor to use a cancer, eg, a cancer described herein (eg, a table). The cancer disclosed in 1) is treated. In certain embodiments, TOR kinase inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the TOR kinase inhibitor is Rad-001 as disclosed herein or in the literature cited in Table 1. In certain embodiments, TOR kinase inhibitors are disclosed, for example, in International Patent Publication No. 2014/085318. In some embodiments, Rad-001 has a structure as disclosed in the publications provided in Table 1 or cited in Table 1. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, pembrolizumab or one of MSB0010718C) is used in combination with Rad-001, wherein the cancer or disorder described herein, eg, Table 1, eg. , Solid tumors, such as sarcoma, lung cancer (eg, non-small cell lung cancer (NSCLC) (eg, NSCLC with squamous epithelium and / or non-squash epithelial tissue)), melanoma (eg, advanced melanoma), digestion. Treats vessel / gastrointestinal cancer, gastric cancer, neurological cancer, prostate cancer, bladder cancer, lung cancer; or hematopoietic tumors such as lymphoma or leukemia.

In some embodiments, an inhibitor of the immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with Rad-001, where Rad-001 is ((1R, 9S, 12S,). 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2-[(1S, 3R, 4R) -4 -(2-Hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza- Tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone).

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an HDM2 ligase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In certain embodiments, HDM2 ligase inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the HDM2 ligase inhibitor is CGM097 as disclosed herein or in the literature cited in Table 1. In some embodiments, the HDM2 ligase inhibitor is disclosed, for example, in International Patent Publication No. 2011/0767686. In some embodiments, the CGM 097 has a structure herein such that it is provided in Table 1 or disclosed in a publication cited in Table 1. In certain embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, pembrolizumab or one of MSB0010718C) is used in combination with CGM097, wherein the cancer or disorder, eg, solids, listed herein, eg, solid. Treat the tumor.

In some embodiments, an inhibitor of the immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with CGM097, where CGM097 is (S) -1- (4-chlorophenyl)-. 7-isopropoxy-6-methoxy-2-(4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl) -trans-cyclohexylmethyl] -amino} phenyl) -1,4 -Dihydro-2H-isoquinoline-3-one.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a PIM kinase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In some embodiments, the PIM kinase inhibitor is LGH447 (also known as PIM447) disclosed herein, eg, Table 1. In some embodiments, PIM kinase inhibitors are disclosed in the publications cited in Table 1. In some embodiments, PIM kinase inhibitors are disclosed, for example, in International Patent Publication No. 2010/026124, European Patent Application EP2344444 and US Patent Publication No. 2010/0056576. In some embodiments, the PIM kinase inhibitor has a structure as provided in Table 1 or disclosed in the literature cited in Table 1. In certain embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, penbrolizumab or one of MSB0010718C) is used in combination with a PIM kinase inhibitor, wherein, for example, the cancers or disorders listed in Table 1. For example, treat hematopoietic tumors such as multiple myeloma, myelodysplastic syndrome, myelodysthesia or non-Hodgkin's lymphoma.

In some embodiments, an inhibitor of the immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with LGH447, where LGH447 is N- (4-((1R, 3S,). 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a HER3 kinase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In certain embodiments, HER3 kinase inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the HER3 kinase inhibitor is LJM716 as disclosed herein or in the literature cited in Table 1. In some embodiments, HER3 kinase inhibitors are disclosed, for example, in International Patent Publication No. 2012/022814 and US Pat. No. 8,735,551. In some embodiments, the LJM716 has a structure as disclosed in the publications provided in Table 1 or cited in Table 1. In some embodiments, the anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprises VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as described in US 8,735,551. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, pembrolizumab or one of MSB0010718C) is used in combination with LJM716, wherein the cancer or disorder, eg, solids, listed herein, eg, solid. Treat tumors such as gastric cancer, esophageal cancer, breast cancer, head and neck cancer, gastric cancer or gastrointestinal / gastrointestinal cancer.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an HDAC inhibitor to use a cancer, eg, a cancer described herein (eg, Table 1). Disclosed in the treatment of cancer). In certain embodiments, HDAC inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the HDAC inhibitor is LBH589 as disclosed herein or in the literature cited in Table 1. In some embodiments, HDAC inhibitors are disclosed, for example, in International Patent Publication 2014/072493 and 2002/022577 and European Patent Application EP1870399. In some embodiments, the LBH 589 has a structure as disclosed in the publications provided in Table 1 or cited in Table 1. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nibolumab, penbrolizumab or one of MSB0010718C) is used in combination with LBH589, wherein the cancer or disorder, eg, solid, as described herein, eg, solid. Tumors such as bone cancer, small cell lung cancer, respiratory / chest cancer, prostate cancer, non-small cell lung cancer (NSCLC), neurological cancer, gastric cancer, melanoma, breast cancer, pancreatic cancer, colorectal cancer, kidney cancer or Head and neck cancer or liver cancer; or treat hematopoietic tumors, such as multiple myeloma, hematopoietic disorders, myelodystrophy syndrome, lymphoma (eg, non-hodgkin lymphoma) or leukemia (eg, myeloid leukemia).

In some embodiments, an inhibitor of the immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with LBH589, where LBH589 is (E) -N-hydroxy-3- (4). -(((2- (2-Methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a Janus kinase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In certain embodiments, Janus kinase inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the Janus kinase inhibitor is INC424 as disclosed herein or in the literature cited in Table 1. In some embodiments, Janus kinase inhibitors are disclosed, for example, in International Patent Publication Nos. 2007/070514 and 2014/018632, European Patent Application EP2474545 and US Pat. No. 7,598,257. In some embodiments, the INC424 has a structure herein such that it is provided in Table 1 or disclosed in a publication cited in Table 1. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, pembrolizumab or one of MSB0010718C) is used in combination with INC424 to use here, for example, the cancer or disorder described in Table 1, eg, solid. Tumors such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer; or hematopoietic tumors such as multiple myeloma, lymphoma (eg non-Hodikin lymphoma) or leukemia (eg myeloid leukemia, lymphocytic leukemia) To treat. In some embodiments, the cancer is identified as having or having a JAK mutation. In some embodiments, the JAK mutation is a JAK2 V617F mutation.

In some embodiments, an inhibitor of the immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with INC424, where INC424 is (3R) -3-cyclopentyl-3- [4. -(7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an FGF receptor inhibitor to use a cancer, eg, a cancer described herein (eg, eg). The cancers disclosed in Table 1) are treated. In certain embodiments, FGF receptor inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the FGF receptor inhibitor is BUW078 or BGJ398 as disclosed herein or in the literature cited in Table 1. In some embodiments, the FGF receptor inhibitor, eg, BUW078 or BGJ398, has a structure (compound or general formula) as disclosed herein, eg, in a publication provided in Table 1 or cited in Table 1. Have. In some embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with BUW078 or BGJ398, wherein the cancers listed herein, eg, solid tumors, eg, gastrointestinal / gastrointestinal cancer; or Treat blood cancer.

In some embodiments, an inhibitor of the immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with BUW078, where BUW078 is 8- (2,6-difluoro-3,5). -Dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide.

In certain embodiments, any combination of the above is one or more of the following second agents, eg, one or more of the additional compounds shown in Table 1 (eg, EGF receptor inhibitors, c-MET inhibitors, as described herein). Agents, ALK inhibitors, CDK4 / 6 inhibitors, PI3K inhibitors, BRAF inhibitors, CAR T cell inhibitors, MEK inhibitors or one or more of BCR-ABL inhibitors) may be further included.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with an EGF receptor inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, EGF receptor inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the EGF receptor inhibitor is such as provided in EGF816 or herein (eg, in the publications cited in Table 1). In some embodiments, the EGF receptor inhibitor, eg, EGF816, has a structure (compound or general formula) herein, eg, as provided in Table 1 or disclosed in a publication cited in Table 1. In some embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with EGF816 to include the cancers listed herein, eg, solid tumors, eg, lung cancer (eg, non-small cell lung cancer). (NSCLC)), treat lymphoma or neuroblastoma.

In some embodiments, the cancer is NSCLC and is characterized by one or more of the aberrant activation, amplification or mutation of the epidermal growth factor receptor (EGFR). In some embodiments, the cancer is NSCLC, where NSCLC is characterized by having EGFR exon 20 insertion, EGFR exon 19 deletion, EGFR L858R mutation, EGFR T790M or any combination thereof. In some embodiments, the combination is for use in the treatment of NSCLC, wherein the NSCLC has an EGFR exon 20 insertion, an EGFR exon 19 deletion, an EGFR L858R mutation, an EGFR T790M or any combination thereof. Characterized. In some embodiments, NSCLC is characterized by having the L858R and T790M variants of EGFR. In other embodiments, NSCLC is characterized by having an EGFR exon 20 insertion and a T790M mutation in EGFR. In yet another embodiment, NSCLC is characterized by having an EGFR exon 19 deletion and a T790M mutation in EGFR. In another embodiment, NSCLC is characterized by having an EGFR mutation selected from the group consisting of exon 20 insertion, exon 19 deletion, L858R mutation, T790M mutation and any combination thereof.

In some embodiments, the lymphoma (eg, anaplastic large cell lymphoma or non-Hodgkin's lymphoma) is identified as having or having an ALK translocation, eg, an EML4-ALK fusion.

In some embodiments, the EGF 816 is administered at an oral dose of about 50-500 mg, such as about 100 mg-400 mg, about 150 mg-350 mg or about 200 mg-300 mg, such as about 100 mg, 150 mg or 200 mg. The dosing schedule may change, for example, from every other day to every day, twice or three times a day. In some embodiments, EGF816 is administered once daily at an oral dose of about 100-200 mg. In certain embodiments, EGF816 is administered at a dose of 75 mg, 100 mg, 150 mg, 225 mg, 150 mg, 200 mg, 225 mg, 300 mg or 350 mg. These doses may be administered once daily. For example, EGF816 can be administered at a dose of 100 mg or 150 mg once daily. In aspects of this combination, nivolumab is administered at a dose of about 1 mg / kg to 5 mg / kg, eg, 3 mg / kg, approximately once to 2 weeks, 3 weeks or 4 weeks over a 60 minute period. Can be administered once.

In other embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or otherwise). (In combination with the immunomodulatory agent of) is used in combination with a c-MET inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, c-MET inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the c-MET inhibitor is INC280 (formerly known as INCB28060) as disclosed herein or in the literature cited in Table 1. In some embodiments, the c-MET inhibitor, eg, INC280, has a structure (compound or general formula) herein, as disclosed herein, eg, in a publication provided in Table 1 or cited in Table 1. In certain embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with INC280 to include the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). It treats polymorphontic glioblastoma (GBM), kidney cancer, liver cancer (eg, hepatocellular carcinoma) or gastric cancer. In some embodiments, the cancer has or is identified as having or having a c-MET mutation (eg, c-MET mutation or c-MET amplification).

In some embodiments, INC280 is administered at an oral dose of about 100-1000 mg, such as about 200 mg-900 mg, about 300 mg-800 mg or about 400 mg-700 mg, such as about 400 mg, 500 mg or 600 mg. The dosing schedule may change, for example, from every other day to every day, twice or three times a day. In some embodiments, INC280 is administered twice daily at an oral dose of about 400-600 mg.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with an Alk inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, Alk inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the Alk inhibitor is LDK378 (Ceritinib (also known as Dicadia®), as described, for example, here or in the publications cited in Table 1. Alk Inhibitor. The agent, eg, LDK378, has a structure (compound or general formula) herein as disclosed, for example, in the publications provided in Table 1 or cited in Table 1.

In certain embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with LDK378 for the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treat lymphomas (eg, undifferentiated large cell lymphoma or non-Hodgkin's lymphoma), inflammatory myofibroblastic tumor (IMT) or neuroblastoma. In some embodiments, NSCLC is stage IIIB or IV NSCLC or relapsed locally advanced or metastatic NSCLC. In some embodiments, the cancer (eg, lung cancer, lymphoma, inflammatory myofibroblast tumor or neuroblastoma) is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion. In some embodiments, the ALK fusion is an EML4-ALK fusion, eg, an EML4-ALK fusion described herein. In another embodiment, the ALK fusion is an ALK-ROS1 fusion. In some embodiments, the cancer is advanced or resistant or resistant to a ROS1 or ALK inhibitor, eg, an ALK inhibitor other than LDK378. In some embodiments, the cancer is advanced or resistant or resistant to crizotinib. In some embodiments, the subject is an ALK untreated patient, eg, a human patient. In another embodiment, the subject is a patient pretreated with an ALK inhibitor, eg, a human patient. In another embodiment, the subject is a patient pretreated with LDK378, eg, a human patient.

In some embodiments, LDK378 and nivolumab are administered to ALK untreated patients. In another embodiment, LDK378 and nivolumab are administered to a patient pretreated with an ALK inhibitor. In yet another embodiment, LDK378 and nivolumab are administered to patients pretreated with LDK378.

In some embodiments, LDK378 is administered at an oral dose of about 100-1000 mg, such as about 150 mg-900 mg, about 200 mg-800 mg, about 300 mg-700 mg or about 400 mg-600 mg, such as about 150 mg, 300 mg, 450 mg, 600 mg or 750 mg. Administer. In some embodiments, LDK378 is administered at an oral dose of about 750 mg or less, eg, about 600 mg or less, eg, about 450 mg or less. In some embodiments, LDK378 is administered with a diet. In another embodiment, the administration is hungry. The dosing schedule may change, for example, from every other day to every day, twice or three times a day. In certain embodiments, LDK378 is administered daily. In some embodiments, LDK378 is administered at a daily oral dose of about 150 mg to 750 mg with food or on an empty stomach. In some embodiments, LDK378 is administered at an oral dose of 750 mg daily on an empty stomach. In some embodiments, LDK378 is administered in capsules or tablets at a daily oral dose of 750 mg. In another embodiment, LDK378 is administered in capsules or tablets at an oral dose of about 600 mg daily. In some embodiments, LDK378 is administered in capsules or tablets at an oral dose of about 450 mg daily.

In some embodiments, LDK378 is administered at a dose of about 450 mg and nivolumab is administered at a dose of about 3 mg / kg. In another embodiment, the LDK 378 dose is 600 mg and the nivolumab dose is 3 mg / kg. In some embodiments, LDK378 is administered with a low-fat diet.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with a CDK4 / 6 inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, CDK4 / 6 inhibitors are disclosed herein, eg, in Table 1. In some embodiments, it is LEE011 (also known as Ribociclib®), eg, as described herein or in the publications cited in Table 1. In some embodiments, the CDK4 / 6 inhibitor, eg, LEE011, has a structure (compound or general formula) herein, eg, as provided in Table 1 or disclosed in a publication cited in Table 1. In certain embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with LEE011 to include the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treat neurogenic cancer, melanoma or breast cancer or hematopoietic tumors, such as lymphoma.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with a PI3K inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, PI3K inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the PI3K inhibitor is, for example, BKM120 or BYL719 disclosed herein or in the publications cited in Table 1. In some embodiments, the PI3K inhibitor, eg, BKM120 or BYL719, has a structure (compound or general formula) as disclosed herein, eg, in a publication provided in Table 1 or cited in Table 1. In some embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with BKM120 or BYL719 to treat the cancers or disorders listed herein, eg, Table 1. In some embodiments, the cancer or disorder is, for example, a solid tumor, eg, lung cancer (eg, non-small cell lung cancer (NSCLC)), prostate cancer, endocrine cancer, ovarian cancer, melanoma, bladder cancer, female reproductive system cancer, Select from gastrointestinal / gastrointestinal cancer, colorectal cancer, polygliostomy (GBM), head and neck cancer, gastric cancer, pancreatic cancer or breast cancer; or hematopoietic tumors such as leukemia, non-Hodgkin lymphoma; or hematopoietic development disorders Will be done.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with a BRAF inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, BRAF inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the BRAF inhibition is LGX818, eg, as described herein or in the publications cited in Table 1. In some embodiments, the BRAF inhibitor, eg, LGX818, has a structure (compound or general formula) herein, as disclosed, for example, in the publications provided in Table 1 or cited in Table 1. In certain embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with LGX818 to include the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treats melanoma, such as advanced melanoma, thyroid cancer, such as papillary thyroid cancer or colorectal cancer. In some embodiments, the cancer is identified as having or having a BRAF mutation (eg, BRAF V600E mutation), BRAF wild type, KRAS wild type or activated KRAS mutation. Cancer can be early, middle or late.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with CAR T cells targeting CD19 to treat cancer, eg, the cancers listed herein (eg, the cancers disclosed in Table 1). In some embodiments, the CAR T cell targeting CD19 is, for example, CTL019, which is disclosed in Table 1 or in the literature cited in Table 1. In some embodiments, CAR T cells targeting CD19, such as CTL019, have a structure (compound or general formula) as disclosed herein, eg, in a publication provided in Table 1 or cited in Table 1. Has. In some embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with CTL019 to treat the cancers listed in Table 1, such as solid tumors or hematopoietic tumors, such as lymphocytic leukemia or non-Hodgkin's lymphoma. ..

In some embodiments, the CAR T cell targeting CD19 has the USAN name TISAGENLECLEUCEL-T. CTL019 is produced by gene modification of T cells that mediate stable insertion by transduction with a self-inactivating, replication-deficient lentivirus (LV) vector containing the CTL019 transgene under the control of the EF-1alpha promoter. CTL019 is a mixture of transgene positive and negative T cells delivered to a subject based on the percentage of transgene positive T cells.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with a MEK inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, MEK inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the MEK inhibitor is MEK162, eg, disclosed herein or in the publications cited in Table 1. In some embodiments, the MEK inhibitor, eg, MEK162, has a structure (compound or general formula) herein, eg, as disclosed in the publications provided in Table 1 or cited in Table 1. In some embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with MEK162 to treat the cancers listed in Table 1. In other embodiments, the cancers or disorders treated with this combination are melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematopoietic tumor or renal cell carcinoma, multilineage. Select from genetic disorders, gastrointestinal / gastrointestinal cancer, gastric cancer or colorectal cancer; or rheumatoid arthritis. In some embodiments, the cancer is identified as having or having a KRAS mutation.

In some embodiments, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nivolumab or pembrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1 antibody (eg, MSB0010718C) (alone or other). (In combination with an immunomodulator) is used in combination with a BCR-ABL inhibitor to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1). In certain embodiments, BCR-ABL inhibitors are disclosed herein, eg, in Table 1. In some embodiments, the BCR-ABL inhibitor is AMN-107 (nilotinib, also known as trade name Tasigna) disclosed herein or in the publications cited in Table 1. In some embodiments, the AMN-107 has a structure (compound or general formula) herein as disclosed, for example, in a publication provided in Table 1 or cited in Table 1. In some embodiments, one of nibolumab, penbrolizumab or MSB0010718C is used in combination with AMN-107 for the cancers or disorders listed in Table 1, such as solid tumors, such as neurological cancer, leukemia, digestive organs / Treats gastrointestinal cancer, colorectal cancer, head and neck cancer; or hematopoietic tumors such as chronic myelogenous leukemia (CML), lymphocytic leukemia, myelogenous leukemia; Parkinson's disease; or pulmonary hypertension.

Cancers and Subjects In certain embodiments of the compositions and methods described herein, a proliferative disorder or condition, eg, cancer, is either a solid tumor, a soft tissue tumor (eg, hematological malignancies, leukemia, lymphoma or myeloma) or said cancer. Including, but not limited to, metastatic lesions. In some embodiments, the cancer is a solid tumor. Examples of solid tumors are lung, breast, ovary, lymphatic system, digestive organs (eg colon), anus, genital and urogenital tracts (eg kidney, urinary epithelium, bladder cells, prostate), pharynx, CNS (eg colon). , Brain, nerve or glial cells), head and neck, skin (eg, melanoma) and malignant tumors of various organ systems such as those affecting the pancreas, such as sarcoma, adenocarcinoma and carcinoma and colon cancer, rectal cancer, Includes, but is not limited to, adenocarcinomas including, but not limited to, malignant tumors such as renal cell carcinoma, liver cancer, non-small cell lung cancer, small bowel cancer and esophageal cancer. The cancer can be early, intermediate, late or metastatic cancer.

In some embodiments, the cancer is selected from the cancers disclosed in Table 1. For example, the cancer is a solid tumor, eg, lung cancer (eg, non-small cell lung cancer (NSCLC) (eg, NSCLC with squamous epithelium and / or non-splasia epithelial histology)), colorectal cancer, melanoma (eg, eg). Advanced melanoma), head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC), gastrointestinal / gastrointestinal cancer, gastric cancer, neurogenic cancer, glioblastoma (eg, polymorphic glioblastoma), ovary Cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, liver cancer; breast cancer, anal cancer, gastroesophageal cancer, thyroid cancer, cervical cancer; or blood cancer (eg, hodgkin lymphoma, non-hodgkin lymphoma, lymphocytic leukemia or Can be selected from (selected from myeloid leukemia).

In some embodiments, the cancer is a colon cancer, eg, a colon cancer that expresses IAP, eg, human IAP. The human IAP family includes, for example, NAIP, XIAP, cIAP1, cIAP2, ILP2, BRUCE, surviving and living.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC), eg, ALK + NSCLC. As used herein, the term "ALK + non-small cell lung cancer" or "ALK + NSCLC" has activation (eg, constitutive activation) undifferentiated lymphoma kinase activity or rearrangement of the undifferentiated lymphoma kinase (ALK) gene. NSCLC with translocation. In general, patients with ALK + NSCLC are generally younger, lighter (eg, <10 packs per year) smoking history or no smoking history, and lower US Eastern Cooperative Oncology Group activity compared to the general NSCLC population. Has indicators or also has more aggressive disease and therefore experiences rapid disease progression (Shaw et al. J Clin Oncol. 2009; 27 (26): 4247-4253; Sasaki et al. Eur J Cancer. 2010; 46 (10): 1773-1780; Shaw et al. N Engl J Med. 2013; 368 (25): 2385-2394; Socinski et al. J Clin Oncol. 2012; 30 (17): 2055-2062; Yang et al. J Thorac Oncol. 2012; 7 (1): 90-97).

In some embodiments, cancer, such as NSCLC, has an ALK gene rearrangement or translocation. In some embodiments, rearrangement or translocation of the ALK gene leads to fusion (eg, fusion upstream of the ALK promoter region). In some embodiments, fusion results in constitutive activation of kinase activity.

In some embodiments, the fusion is an EML4-ALK fusion. Examples of EML4-ALK fusion proteins are E13; A20 (V1), E20; A20 (V2), E6a / b; A20 (V3a / b), E14; A20 (V4), E2a / b; A20 (V5a / b). ), E13b; A20 (V6), E14; A20 (V7), E15; A20 (“V4”) or E18; A20 (V5), but not limited to (Choi et al. Cancer Res. 2008; 68). (13): 4971-6; Horn et al. J Clin Oncol. 2009; 27 (26): 4232-5; Koivunen et al. Clin Cancer Res. 2008; 14 (13): 4275-83; Soda et al. Nature. 2007; 448 (7153): 561-6; Takeuchi et al. Clin Cancer Res. 2008; 14 (20): 6618-24; Takeuchi et al. Clin Cancer Res. 2009; 15 (9): 3143-9 Wong et al. Cancer. 2009 Apr 15; 115 (8): 1723-33).

In some embodiments, the ALK gene fuses with a non-EML4 partner. In some embodiments, the fusion is a KIF5B-ALK fusion. In another embodiment, the fusion is a TFG-ALK fusion. Examples of KIF5B-ALK and TFG-ALK fusions are, for example, in Takeuchi et al. Clin Cancer Res. 2009; 15 (9): 3143-9, Rikova et al. Cell. 2007; 131 (6): 1190-203. It has been arrived.

Cancer cells with ALK gene rearrangements or translocations or ALK gene rearrangements or translocations can be detected, for example, using an ALK break apartment probe, eg, using fluorescence in situ hybridization (FISH).

The methods and compositions disclosed herein are useful in the treatment of metastatic lesions associated with said cancer.

In other embodiments, the subject is a mammal, eg, a primate, preferably a higher primate, eg, a human (eg, a patient with or at risk of the disorder described herein). In some embodiments, the subject needs to enhance an immune response. In some embodiments, the subject has or is at risk of having or having a disorder described herein, eg, cancer as described herein. In some embodiments, the subject is or is at risk of an immune disorder. For example, the subject was or received chemotherapy treatment and / or radiation therapy. Apart from or in addition to this, the subject is at or at risk of having an immune disorder as a result of infection.

In some embodiments, the subject (eg, lung cancer (eg, non-small cell lung cancer), lymphoma (eg, undifferentiated large cell lymphoma or non-Hodgkin lymphoma), subject with inflammatory myofibroblast tumor or neuroblastoma). , Other ALK inhibitors and / or ROS1 inhibitors, eg, treated or treated with crizotinib. For example, crizotinib can be administered at an oral dose of 750 mg or less, eg, 600 mg or less, eg, 450 mg or less per day.

In other embodiments, the subject or cancer (eg, lung cancer (eg, non-small cell lung cancer), lymphoma (eg, undifferentiated large cell lymphoma or non-Hodgkin's lymphoma), inflammatory myofibroblast tumor or neuroblastoma) , Other ALK inhibitors and / or ROS1 inhibitors, eg, are advanced or resistant or resistant to crizotinib.

In yet another embodiment, the subject or cancer (eg, lung cancer (eg, non-small cell lung cancer), lymphoma (eg, undifferentiated large cell lymphoma or non-Hodgkin's lymphoma), inflammatory myofibroblast tumor or neuroblastoma). Are at risk of developing or gaining resistance or resistance to other ALK inhibitors and / or ROS1 inhibitors, such as crizotinib.

In other embodiments, the subject or cancer is at risk of being resistant or resistant to or acquiring resistance to a tyrosine kinase inhibitor (TKI), eg, an EGFR tyrosine kinase inhibitor.

In some embodiments, the subject or cancer has no detectable EGFR mutation, KRAS mutation, or both.

In some embodiments, the subject has previously been treated with PD-1.

In some embodiments, the subject is identified as having or having a tumor with high PD-L1 levels or expression and / or one or more of tumor-infiltrating lymphocytes (TIL) +. In some embodiments, the subject is identified as having or having a tumor with high PD-L1 levels or expression and TIL +. In certain embodiments, the methods described herein further describe the identification of a subject based on having a tumor with a high PD-L1 level or expression and / or one or more of TIL +. In certain embodiments, the methods described herein further describe the identification of a subject based on having a tumor with high PD-L1 levels or expression and TIL +. In some embodiments, tumors that are TIL + are positive for CD8 and IFNγ. In some embodiments, the subject is identified as having or having a high percentage of cells that are positive for one or more of PD-L1, CD8 and / or IFNγ. In some embodiments, the subject is identified as having or having a high percentage of cells that are positive for all of PD-L1, CD8 and IFNγ.

In certain embodiments, the methods described herein further describe the identification of a subject based on having a high percentage of cells positive for one or more of PD-L1, CD8 and / or IFNγ. In certain embodiments, the methods described herein further describe the identification of a subject based on having a high percentage of cells positive for all of PD-L1, CD8 and IFNγ. In some embodiments, the subject is one or more of PD-L1, CD8 and / or IFNγ and lung cancer, such as squamous cell lung cancer or lung adenocarcinoma; head and neck cancer; squamous epithelial cell cervical cancer; gastric cancer; thyroid cancer; and / Or identified as having or having one or more of melanoma. In certain embodiments, the methods described herein further include one or more of PD-L1, CD8 and / or IFNγ and lung cancer, such as squamous cell lung cancer or lung adenocarcinoma; head and neck cancer; squamous epithelial cell cervical cancer; Further describe the identification of subjects based on having one or more of gastric cancer; thyroid cancer; and / or melanoma.

Dosage and Administration The dosage and treatment regimen for the agents described herein may be determined by one of ordinary skill in the art.

In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 1-30 mg / kg, eg, about 5-25 mg / kg, about 10-20 mg / kg, about 1-5 mg / kg or about 3 mg / kg. Administer by injection (eg, subcutaneously or intravenously). The dosing schedule can vary from once a week to once every two weeks, three or four weeks. In some embodiments, the anti-PD-1 antibody molecule is administered biweekly at a dose of about 10-20 mg / kg.

In some embodiments, an anti-PD-1 antibody molecule, such as nivolumab, is administered intravenously every two weeks at a dose of about 1 mg / kg to 3 mg / kg, such as about 1 mg / kg, 2 mg / kg or 3 mg / kg. do. In some embodiments, an anti-PD-1 antibody molecule, such as nivolumab, is administered intravenously at a dose of about 2 mg / kg at 3-week intervals. In some embodiments, nivolumab is administered at a dose of about 1 mg / kg to 5 mg / kg, eg, 3 mg / kg, approximately once to 2 weeks, 3 weeks or 4 weeks for a period of 60 minutes. Can be administered.

The combination therapies described herein are systemically (eg, orally, non-enterally, subcutaneously, intravenously, rectal, intramuscularly, intraperitoneally, intranasally, transdermally or inhaled or placed intracavitarily in a subject. ), Can be administered topically or by application to mucous membranes such as the nose, throat and bronchi.

In some embodiments, the anti-PD-1 antibody molecule is administered intravenously. In certain embodiments, in combination therapy, one or more agents listed in Table 1, such as an IAP inhibitor or LCL161, are orally administered. In certain embodiments, the anti-PD-1 antibody molecule is administered with the agents listed in Table 1, eg, an IAP inhibitor or LCL161, eg, orally, at least 1 day, 2 days, 3 days, 4 days, 5 days. , 6 or 7 days, eg, 3 days later, eg, intravenously. In certain embodiments, the anti-PD-1 antibody component is administered, eg, orally, the agents listed in Table 1, eg, an IAP inhibitor or LCL161, at least 1 day, 2 days, 3 days, 4 days, 5 days. Administer daily, 6 or 7 days, eg, 3 days prior, eg, intravenously. In yet another embodiment, the anti-PD-1 antibody molecule is administered, eg, intravenously, on the same day that one or more agents listed in Table 1, eg, IAP inhibitor or LCL161, are administered, eg, orally. Administer. In some embodiments, administration of an anti-PD-1 antibody molecule and one or more agents listed in Table 1, eg, an IAP inhibitor or LCL161, is solid compared to administration of each of these agents as monotherapy. It results in enhanced reduction of tumors, eg colon cancer. In some embodiments, the concentration of the agents listed in Table 1, eg, IAP inhibitor or LCL161, required to achieve inhibition, eg, growth inhibition, in combination therapy is lower than the therapeutic dose of the agent as monotherapy. For example, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower. In other embodiments, in combination therapy, the concentration of anti-PD-1 antibody molecule required to achieve inhibition, eg, growth inhibition, is lower than the therapeutic dose of anti-PD-1 antibody molecule as therapeutic therapy, eg, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower.

The methods and compositions described herein can be used in combination with additional agents or therapeutic modality. The combination therapy can be administered simultaneously or sequentially in any order. Any combination and sequence of anti-PD-1 or PD-L1 antibody molecules and other therapeutic agents, methods or modality (eg, as described herein) can be used. Combination therapy can be administered during active phase disorder or remission or hypoactive phase disease. Combination therapy can be administered prior to other treatments, at the same time as the treatment, or after treatment or during remission of the disorder.

In certain embodiments, the methods and compositions described herein can be used with other antibody molecules, chemotherapy, other anticancer therapies (eg, targeted anticancer therapies, gene therapies, viral therapies, RNA therapies, bone marrow transplants, nanotherapies). Or tumor lytic agents), cytotoxic agents, immune-based therapies (eg, cytokines or cell-based immunotherapy), surgical procedures (eg, breast tumor resection or mastectomy) or radiation methods or a combination of any of the above. Administer in combination with 1 or more of. Further treatment can be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the further treatment is an enzyme inhibitor (eg, a small molecule enzyme inhibitor) or a metastasis inhibitor. Examples of cytotoxic agents that can be administered in combination are microtubule inhibitors, topoisomerase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, binca alkaloids, inserts, agents that can interfere with signaling pathways. Includes agents that promote apoptosis, proteosome inhibitors and radiation (eg, local or systemic irradiation (eg, gamma irradiation)). In other embodiments, further treatment is surgery or radiation or a combination thereof. In other embodiments, the further treatment is a treatment that targets the mTOR pathway, an HSP90 inhibitor or a tubulin inhibitor.

Apart from or in addition to the above combinations, the methods and compositions described herein can be administered in combination with a vaccine, eg, a therapeutic cancer vaccine; or one or more of other forms of cellular immunotherapy.

In other embodiments, the combination therapy is used in combination with one, two or all of oxaliplatin, leucovorin or 5-FU (eg, FOLFOX co-treatment). Separately or in addition to this, the combination further comprises a VEGF inhibitor (eg, a VEGF inhibitor as disclosed herein). In some embodiments, the cancer treated in combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematopoietic tumor or renal cell carcinoma. Cancer can be early, middle or late.

In other embodiments, the combination therapy is administered with a tyrosine kinase inhibitor (eg, axitinib) to treat renal cell carcinoma and other solid tumors.

In another embodiment, the combination therapy is administered with a 4-1BB receptor targeting agent (eg, an antibody that stimulates signal transduction via 4-1BB (CD-137), eg, PF-2566). In some embodiments, the combination therapy is administered in combination with a tyrosine kinase inhibitor (eg, axitinib) and a 4-1BB receptor targeting agent.

All publications, patent applications, patents and other references described herein are hereby incorporated by reference in their entirety.

Other properties, objects and advantages of the invention are evident in the specification and drawings as well as in the claims.

FIG. 3 shows a graph of flow cytometry of PD-L1 surface expression in EBC-1 cells treated or untreated with INC280 in vitro. EBC-1 cells are non-small cell lung cancer cells with cMET amplification.

FIG. 3 shows a graphical representation of PD-L1 mRNA expression in Hs.746.T cells in an INC280-treated or untreated tumor xenograft model. Hs.746.T cells are gastric cancer cells with c-MET amplification and c-MET mutations.

FIG. 3 shows a graphical representation of PD-L1 mRNA expression in H3122 cells in the presence or absence of LDK378 in vitro. H3122 cells are non-small cell lung cancer (NSCLC) cells with ALK translocation.

FIG. 3 shows a graphical representation of PD-L1 mRNA expression in LOXIMV1 cells (BRAF mutant melanoma cells) in an LGX818 treated or untreated tumor xenograft model.

FIG. 6 shows a graph showing PD-L1 mRNA expression in HEYA8 cells (KRAS mutant ovarian cancer cells) of a tumor xenograft model treated or untreated with MEK162.

FIG. 6 shows a graphical representation of PD-L1 mRNA expression in UKE-1 cells (JAK2 V617F mutant myeloproliferative neoplasm cells) of an INC424-treated or untreated tumor xenograft model.

Graphical representation of IFN-γ production in stimulated PBMCs treated with unstimulated PBMCs or various concentrations of LCL161 or DMSO controls is shown.

Graphical representation of IL-10 production in stimulated PBMCs treated with unstimulated PBMCs or various concentrations of LCL161 or DMSO controls is shown.

Graphs of FACS analysis of CD4 + T cells from stimulated PMBC in the presence of unstimulated PBMC or various concentrations of LCL161 or DMSO control are shown.

Graphs of FACS analysis of CD8 + T cells from stimulated PMBC in the presence of unstimulated PBMC or various concentrations of LCL161 or DMSO control are shown.

FIG. 3 shows a graphical representation of CyTOF mass cytometry of stimulated PBMCs treated with unstimulated PBMCs or LCL161 or DMSO.

The graph display of the expression signature related to the T cell from the mouse transplanted with MC38 cell is shown. Mice were treated with LCL161, anti-mouse PD-1 or both. In the control group, mice were dosed with the vehicle and isotype (mIgG1).

The graph display of the expression signature related to the dendritic cell from the mouse transplanted with MC38 cell is shown. Mice were treated with LCL161, anti-mouse PD-1 or both. In the control group, mice were dosed with the vehicle and isotype (mIgG1).

The graph display of the expression signature related to the macrophage from the mouse transplanted with MC38 cells is shown. Mice were treated with LCL161, anti-mouse PD-1 or both. In the control group, mice were dosed with the vehicle and isotype (mIgG1).

The graph display of the chemokine expression signature from the mouse transplanted with MC38 cells is shown. Mice were treated with LCL161, anti-mouse PD-1 or both. In the control group, mice were dosed with the vehicle and isotype (mIgG1).

A graph display of tumor volume in an example of treatment schedule and mice transplanted with MC38 cells is shown. Mice were treated with LCL161, anti-mouse PD-1 or both. In this treatment schedule, anti-mouse PD-1 was administered 3 days after LCL161 administration. In the control group, mice were dosed with the vehicle and isotype (mIgG1).

Other treatment schedule examples and a graph display of tumor volume in mice transplanted with MC38 cells are shown. Mice were treated with LCL161, anti-mouse PD-1 or both. In this treatment schedule, LCL161 and anti-mouse PD-1 were co-administered. In the control group, mice were dosed with the vehicle and isotype (mIgG1).

The order of drug administration of patients who oxidize to Phase II clinical trials treated with EGF816 and nivolumab is shown.

Brief Description of Table Table 1 is a summary of selective therapeutic agents that can be administered in combination with the immunomodulators listed herein (eg, one or more of the activators of the co-stimulatory molecule and / or the inhibitors of the immune checkpoint molecule). Is. Table 1 provides, from left to right, the following: names and / or designations of second therapeutic agents, compound structures, patent gazettes disclosing compounds, indications / use examples and general structures. ..

Table 2 shows the clinical trial objectives and related endpoints of the combination of EGF816 and nivolumab in adult patients with EGFR mutant non-small cell lung cancer in Phase II, multicenter, open-label clinical trials.

Table 3 shows the dose and treatment schedule for the combination of EGF816 and nivolumab in adult patients with EGFR mutant non-small cell lung cancer in Phase II, multicenter, open-label clinical trials.

Detailed Description A combination of an immunomodulator (eg, one or more of a co-stimulatory molecule activator and / or an immune checkpoint molecule inhibitor) and a second therapeutic agent selected from one or more of the agents listed in Table 1. The methods and compositions, including, are disclosed. Immunotherapy alone may be effective for many indications (eg, melanoma). However, it is not curative for most patients. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5) or CTLA-4). 1 or more of the inhibitors) can be combined with a second therapeutic agent selected from one or more of the agents listed in Table 1 (eg, 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2. Rigase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) Histon deacetylase (HDAC) inhibitor; 7) Janus kinase inhibitor; 8) FGF receptor inhibitor; 9) EGF receptor Inhibitors; 10) c-MET inhibitors; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, targeting CD19) CAR T cells); 16) MEK inhibitors; or 17) BCR-ABL inhibitors selected from one or more). The combinations described herein can provide beneficial effects, such as enhanced anti-cancer effects, toxicity reduction and / or side effect reduction, in the treatment of cancer, for example. For example, immunomodulators, second therapeutic agents, or both can be administered at the low doses required to achieve the same therapeutic effect compared to monotherapy.

The term "inhibitor" or "inhibitor" refers to a molecule, eg, a parameter of an immune checkpoint inhibitor, eg, a decrease in activity. Activity, eg, PD-1, PD-L1, c-MET, ALK, CDK4 / 6, PI3K, BRAF, FGFR, MET or BCR-ABL, eg, at least 5%, 10%, 20% of the activity. 30%, 40% or more inhibition is included in this term, for example. Therefore, the inhibition need not be 100%.

The term "programmed death 1" or "PD-1" includes isoforms, mammals such as human PD-1, species homologues of human PD-1, and analogs comprising at least one common epitope with PD-1. The amino acid sequence of PD-1, eg, human PD-1, is known in the art, eg, Shinohara T et al. (1994) Genomics 23 (3): 704-6; Finger LR, et al. Gene (1997). ) See 197 (1-2): 177-87.

The term "PD-ligand 1" or "PD-L1" includes isoforms, mammals such as human PD-1, species homologues of human PD-L1, and analogs comprising at least one common epitope with PD-L1. The amino acid sequence of PD-L1, for example human PD-L1, is known in the art.

The term "lymphocyte activation gene 3" or "LAG-3" refers to all isoforms, mammals such as human LAG-3, species homologues of human LAG-3 and analogs comprising at least one common epitope with LAG-3. including. Amino acid and nucleotide sequences of LAG-3, eg, human LAG-3, are known in the art and see, eg, Triebel et al. (1990) J. Exp. Med. 171: 1393-1405.

As used herein, "TIM-3" refers to a transmembrane receptor protein expressed in Th1 (T helper 1) cells. TIM-3 has a role in the regulation of immunity and tolerance in vivo (see Hastings et al., Eur J Immunol. 2009 Sep; 39 (9): 2492-501).

The term "carcinoembryonic antigen-related cell adhesion molecule" or "CEACAM" refers to all family members (eg CEACAM-1, CEACAM-3 or CEACAM-5), isoforms, mammals such as human CEACAM, human CEACAM. Includes species homologs and analogs containing CEACAM and at least one common epitope. The amino acid sequences of CEACAM, eg, human CEACAM, can be found in the art, eg, Hinoda et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85 (18), 6959-6963; Zimmermann W. et al. (1987). Proc. Natl. Acad. Sci. U.S.A. 84 (9), 2960-2964; Thompson J. et al. (1989) Biochem. Biophys. Res. Commun. 158 (3), 996-1004.

Further terms are defined below and throughout the present application.
The singular representation used herein means one or more than one (eg, at least one) of the grammatical object.

The term "or" means the terms "and / or" and is used interchangeably with them, unless the context clearly concludes.

“Approximately” and “approximately” generally mean an acceptable degree of error in the measured quality, taking into account the nature or accuracy of the measurement. Examples of degrees of error are within 20 percent (%) of a value or range of values, generally within 10 percent, and more generally within 5 percent.

The compositions and methods of the invention are polypeptides and nucleic acids having a particular sequence or a sequence that is substantially identical or similar thereto, eg, a sequence that is at least 85%, 90%, 95% or more identical to the particular sequence. Including. In the context of amino acid sequences, the term "substantially identical" is used here in the second amino acid sequence such that the first and second amino acid sequences may have a common structural domain and / or common functional activity. A primary amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical or ii) conservative substitutions with the aligned amino acid residues. For example, at least about 85%, 90% with a control sequence, eg, the sequence provided herein. An amino acid sequence comprising a common structural domain with 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity.

In the context of nucleotide sequences, the term "substantially identical" is used herein such that the first and second nucleotide sequences encode a polypeptide having common functional activity or a common structural polypeptide domain. Alternatively, a common functional polypeptide activity refers to a first nucleic acid sequence containing a sufficient or minimum number of nucleotides that are identical to the aligned nucleotides in the second nucleic acid sequence. For example, at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a control sequence, eg, a sequence provided herein. A nucleotide sequence having.

The term "functional variant" is a poly having substantially the same amino acid sequence as a naturally occurring sequence or encoded by a substantially identical nucleotide sequence and having one or more of the activities of the naturally occurring sequence. Refers to a peptide.

Calculations of homology or sequence identity between sequences (these terms are used interchangeably herein) are performed as follows.

To determine the percent identity of a two-amino acid sequence or a two-nucleic acid sequence, the sequences are aligned for optimal comparison purposes (eg, for optimal alignment, to one or both of the first and second amino acids or nucleic acid sequences. Gaps can be inserted and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the control sequence alignment for comparison is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, even more preferably at least 70%, 80% of the length of the control sequence. %, 90%, 100%. The amino acid residues or nucleotides at the corresponding amino acid or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecule is identical at that position (the amino acid or nucleic acid "identity" used herein). "Is the same as the amino acid or nucleic acid" homology ").

Percent identity between two sequences is a function of the number of co-located numbers shared by the sequences, taking into account the number of gaps and the length of each gap that needs to be introduced for optimal alignment of the two sequences.

Sequence comparisons and determination of percent identity between two sequences can be achieved using mathematical algorithms. In a preferred embodiment, the percent identity between the two amino acid sequences can be calculated using the Needleman and Wunsch ((1970) J. Mol. Biol. 48: 444-453) algorithm, which is included in the GAP program of the GCG software package. Incorporated (available at www.gcg.com), Blossum 62 matrix or PAM250 matrix and gap loads 16, 14, 12, 10, 8, 6 or 4 and length loads 1, 2, 3, 4, 5 Or use 6. In yet another preferred embodiment, the percent identity between the two nucleotide sequences was determined using the GAP program in the GCG software package (available at http://www.gcg.com) and the NWSgapdna.CMP matrix and gaps. Loads 40, 50, 60, 70 or 80 and length loads 1, 2, 3, 4, 5 or 6 are used. A particularly preferred set of parameters (and those to be used unless otherwise noted) is the Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4 and a frameshift gap penalty of 5.

Percent identity between two amino acid or nucleotide sequences can be determined using the algorithms of E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17) incorporated into the ALIGN program (version 2.0). , PAM120 load residue table, gap length penalty 12 and gap penalty 4 are used.

The nucleic acid and protein sequences described herein can be used, for example, as "query sequences" to perform searches against public databases to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215: 403-10. The BLAST nucleotide search can be performed using the NBLAST program, score = 100, word length = 12 to obtain a nucleotide sequence homologous to the nucleic acid molecule of the invention. A BLAST protein search can be performed with the XBLAST program, score = 50, word length = 3 to obtain an amino acid sequence homologous to the protein molecule of the invention. To obtain a comparatively gapped alignment, Gapped BLAST can be performed as described in Altschul et al., (1997) Nucleic Acids Res. 25: 3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of each program (eg, XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

As used herein, the term "hybridization under low stringency, medium stringency, high stringency or ultra-high stringency conditions" refers to hybridization and washing conditions. Guidance for carrying out hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, NY (1989), 6.3.1-6.3.6, which is incorporated herein by reference. Aqueous and non-aqueous methods are described in the reference and either can be used. The specific hybridization conditions described herein are as follows: 1) Low stringency hybridization conditions at 6 × sodium chloride / sodium citrate (SSC) at about 45 ° C, followed by 0 at at least 50 ° C. 2 wash of .2 x SSC, 0.1% SDS (wash temperature can be raised to 55 ° C. under low stringency conditions); 2) Medium stringency hybridization conditions at 6 x SSC at about 45 ° C., Subsequently wash at 1 or more of 0.2 x SSC, 0.1% SDS at 60 ° C; 3) High stringency hybridization conditions at 6 x SSC at about 45 ° C, followed by 0.2 x SSC at 65 ° C. , 0.1% SDS 1 or higher wash; and preferably 4) ultra-high stringency hybridization conditions are 0.5 M sodium phosphate at 65 ° C, 7% SDS, followed by 0.2 × at 65 ° C. One or more washes of SSC, 1% SDS. The ultra-high stringency condition (4) is a preferable condition and should be used unless otherwise specified.

It is understood that the molecules of the invention may have additional conservative or non-essential amino acid substitutions that have no substantial effect on function.

The term "amino acid" is intended to include both amino and acid functional groups and to include all natural or synthetic molecules that may be included in polymers of naturally occurring amino acids. Examples of amino acids include naturally occurring amino acids; analogs thereof, derivatives and congeners; amino acid analogs with variant side chains; and all stereoisomers of any of the above. The term "amino acid" as used herein includes D- or L-optical isomers and peptide mimetics.

A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. A family of amino acid residues with similar side chains is defined in the art. These families include basic side chains (eg, lysine, arginine, histidine), acidic side chains (eg, aspartic acid, glutamic acid), uncharged polar side chains (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine). , Cysteine), non-polar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta branched side chains (eg, threonine, valine, isoleucine) and aromatic side chains (eg, cysteine). Contains amino acids with tyrosine, phenylalanine, tryptophan, histidine).

The terms "polypeptide", "peptide" and "protein" (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be straight chain or branched chain, may contain modified amino acids and may be interrupted by non-amino acids. The term also includes amino acid polymers that have been modified, eg, have undergone any other manipulation such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation or conjugation with labeling elements. .. Polypeptides may be isolated from natural sources and may be produced from eukaryotic or prokaryotic hosts in favor of recombinant techniques or by synthetic methods.

The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably. These refer to nucleotides of any length, in polymerized form, deoxyribonucleotides or ribonucleotides or analogs thereof. The polynucleotide may be single-stranded or double-stranded, and if it is single-stranded, it may be a coding strand or a non-coding (antisense) strand. Polynucleotides can include modified nucleotides such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides can be interrupted by non-nucleotide elements. Polynucleotides can be further modified after polymerization, such as by conjugation with a labeling element. The nucleic acid can be a recombinant polynucleotide or a polynucleotide of synthetic origin that does not occur in nature or is linked to other polynucleotides in a genomic, cDNA, semi-synthetic or non-natural arrangement.

As used herein, the term "isolation" refers to a substance that has been removed from its original or original environment (eg, its natural environment if it exists naturally). For example, a naturally occurring polynucleotide or a polypeptide present in a living animal is not isolated, but is manually isolated from some or all of the coexisting substances in the natural system. Is isolated. Such a polynucleotide is part of a vector and / or such a polynucleotide or polypeptide is part of a composition, and such a vector or composition is one of the environments in which it is originally found. It is still isolated in that it is not a part.

Various aspects of the invention are described in more detail below. Further definitions are given herein.

Antibody Molecules In certain embodiments, the antibody molecules are mammalian, eg, human, checkpoint molecules such as PD-1, PD-L1, LAG-3, CEACAM (eg, CEACAM-1, -3 and / or -5). ) Or bind to TIM-3. For example, the antibody molecule may be an epitope of PD-1, PD-L1, LAG-3, CEACAM (eg, CEACAM-1, -3 and / or -5) or TIM-3, eg, linear or conformational. It specifically binds to an epitope (eg, an epitope as described herein).

As used herein, the term "antibody molecule" refers to a protein that comprises at least one immunoglobulin variable domain sequence. The term antibody molecule includes, for example, full-length, mature antibodies and antigen-binding fragments of the antibody. For example, the antibody component may include a heavy (H) chain variable domain sequence (here abbreviated as VH) and a light (L) chain variable domain sequence (here abbreviated as VL). In another example, the antibody molecule is Fab, Fab', F (ab') ₂ , Fc, Fd, Fd', Fv, single chain antibody (eg, scFv), single variable domain antibody, bispecific antibody. Like (Dab) (divalent and bispecific) and chimeric (eg, humanized) antibodies, it contains a double (H) chain variable domain sequence and a double (L) chain variable domain sequence, thereby two antigens. It forms a binding site, which can be produced by modification of the entire antibody or can be synthesized with de novo using recombinant DNA technology. These functional antibody fragments maintain their ability to selectively bind to their respective antigens or receptors. Antibodies and antibody fragments can be antibodies of any class, including but not selected for IgG, IgA, IgM, IgD and IgE and any subclass of antibody (eg, IgG1, IgG2, IgG3 and IgG4). The antibody of the present invention may be monoclonal or polyclonal. The antibody can also be a human, humanized, CDR transplanted or in vitro produced antibody. The antibody may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3 or IgG4. The antibody may also have a light chain, for example selected from kappa or lambda.

Examples of antigen-binding fragments include (i) Fab fragment, monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) F (ab') 2 fragment, 2 Fab fragment linked by disulfide cross-linking at the hinge region. Containing, bivalent fragment; (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv fragment consisting of single arm VL and VH domains of antibody, (v) bispecific antibody (dAb) consisting of VH domain. Fragments; (vi) camels or cameled variable domains; (vii) single-chain Fv (scFv), eg Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. See Natl. Acad. Sci. USA 85: 5879-5883); (viii) Includes single domain antibodies. These antibody fragments are obtained using conventional techniques known to those of skill in the art and the fragments are screened for usefulness in the same manner as a complete antibody.

The term "antibody" includes a complete molecule as well as a functional fragment thereof. Constant regions of the antibody can be modified, eg, mutated (eg, Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function or complement function, one or more) to modify the properties of the antibody. Or to reduce).

The antibody molecule can also be a single domain antibody. Single domain antibodies may include antibodies in which the complementarity determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies that naturally lack the light chain, single domain antibodies derived from conventional four chain antibodies, modified antibodies and single domain scaffolds other than those derived from the antibody. The single domain antibody can be of any art or any future single domain antibody. Single domain antibodies can be from any species including, but not limited to, mice, humans, camels, llamas, fish, sharks, goats, rabbits and cows. According to another aspect of the invention, the single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking a light chain. Such single domain antibodies are disclosed, for example, in WO 9404678. For the avoidance of doubt, this variable domain derived from a heavy chain antibody that naturally lacks a light chain is here known as VHH or Nanobody to distinguish it from the conventional VH of 4-chain immunoglobulins. Such VHH molecules can be derived from camelid species such as camelids, llamas, dromedaries, alpaca and guanaco. Other species than Camelids can naturally produce heavy chain molecules lacking a light chain, such VHHs are within the scope of the invention.

The VH and VL regions can be subdivided into more conserved, hypermutable regions called "complementarity determining regions" (CDRs), interspersed with regions called "framework regions" (FR or FW).

The framework area and the degree of CDR are strictly defined by many methods (Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication. No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196: 901-917; and the AbM definition using Oxford Molecular's AbM antibody modeling software). In general, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (see Ed .: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

As used herein, the terms "complementarity determining regions" and "CDRs" refer to sequences of amino acids within antibody variable regions that confer antigen specificity and binding affinity. Generally, each heavy chain variable region has 3 CDRs (HCDR1, HCDR2, HCDR3) and each light chain variable region has 3 CDRs (LCDR1, LCDR2, LCDR3).

The exact amino acid sequence boundaries of a CDR are Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme). , Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme) can be determined using any number of well-known schemes, including those described. The CDRs used here as defined by the "Chothia" numbering scheme are sometimes referred to as "super-variable loops".

For example, under Kabat, CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) and are light chain variable domains (VL). ) Are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). Under Chothia, the CDR amino acids of VH are numbered 26-32 (HCDR1), 52-56 (HCDR2) and 95-102 (HCDR3), and the amino acid residues in VL are 26-32 (LCDR1), 50-52 (LCDR1). It is numbered LCDR2) and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, CDRs are amino acid residues 26-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) in human VH and amino acid residues 24- in human VL. It consists of 34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3).

The "immunoglobulin variable domain sequence" used here refers to an amino acid sequence capable of forming the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of a naturally occurring variable domain amino acid sequence. For example, the sequence may or may not contain one, two or more N-terminal or C-terminal amino acids and may include other modifications that are compatible with the formation of protein structures.

The term "antigen binding site" refers to a portion of an antibody molecule that comprises a determinant that forms an interface that binds to a PD-1 polypeptide or epitope thereof. For proteins (or protein mimetics), the antigen binding site generally comprises one or more loops (of at least 4 amino acids or amino acid mimetics) that form an interface that binds to the PD-1 polypeptide. In general, the antigen binding site of an antibody molecule comprises at least 1 or 2 CDRs and / or a hypervariable loop or more generally at least 3, 4, 5 or 6 CDRs and / or a hypervariable loop.

As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to a preparation of an antibody molecule having a single molecular composition. Monoclonal antibody compositions exhibit single binding specificity and affinity for a particular epitope. Monoclonal antibodies can be produced by hybridoma technology or methods that do not use hybridoma technology (eg, recombinant methods).

An "efficiently human" protein is a protein that does not elicit a neutralizing antibody response, eg, a human anti-mouse antibody (HAMA) response. HAMA can be problematic, for example, in chronic or recurrent disease states, in many situations, for example, with repeated administration of antibody molecules. HAMA responses can cause repeated antibody administration to increase antibody clearance from serum (eg, Saleh et al., Cancer Immunol. Immunother., 32: 180-190 (1990)) and also allergic reactions. May be disabled for (eg, LoBuglio et al., Hybridoma, 5: 5117-5123 (1986)).

The antibody molecule may be a polyclonal antibody or a monoclonal antibody. In other embodiments, the antibody may be produced by recombination, eg, by phage display or combinatorial methods.

Phage display and combinatorial methods for producing antibodies are known in the art (eg, Ladner et al. US Pat. No. 5,223,409; all of which are incorporated herein by reference; Kang et al. International Publication WO92 / 18619; Dower et al. International Publication WO91 / 17271; Winter et al. International Publication WO92 / 20791; Markland et al. International Publication WO92 / 15679; Breitling et al. International Publication WO93 / 01288 Issue; McCafferty et al. International Publication WO 92/01047; Garrard et al. International Publication WO 92/09690; Ladner et al. International Publication WO 90/02809; Fuchs et al. (1991) Bio / Technology 9: 1370-1372 Hay et al. (1992) Hum Antibod Hybridomas 3: 81-85; Huse et al. (1989) Science 246: 1275-1281; Griffths et al. (1993) EMBO J 12: 725-734; Hawkins et al. (1992) J Mol Biol 226: 889-896; Clackson et al. (1991) Nature 352: 624-628; Gram et al. (1992) PNAS 89: 3576-3580; Garrad et al. (1991) Bio / Technology 9: 1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19: 4133-4137; and Barbas et al. (1991) as described in PNAS 88: 7978-7982).

In some embodiments, the antibody is a fully human antibody (eg, an antibody produced in a mouse that has been genetically modified to produce an antibody from a human immunoglobulin sequence) or a non-human antibody, eg, a rodent (mouse or rat). ), Goats, primates (eg monkeys), camel antibodies. Preferably, the non-human antibody is a rodent (mouse or rat antibody). Methods of producing rodent antibodies are known in the art.

Human monoclonal antibodies can be produced using transgenic mice carrying the human immunoglobulin gene rather than mouse systems. Spleen cells from these transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinity for epitopes from human proteins (eg, Wood et al. International Application WO91 / 00906, Kucherlapati et al. PCT Publication WO91 / 10741; Lonberg et al. International Application WO92 / 03918; Kay et al. International Application 92/03917; Lonberg, N. et al. 1994 Nature 368: 856-859; Green, L.L. et al. 1994 Nature Genet. 7: 13-21; Morrison, S.L. et al. 1994 Proc. Natl. Acad. Sci. USA 81: 6851-6855; Bruggeman et al. 1993 Year Immunol 7 : 33-40; Tuaillon et al. 1993 PNAS 90: 3720-3724; Bruggeman et al. 1991 Eur J Immunol 21: 1323-1326).

The antibody can be a variable region or part thereof, such as a CDR produced in a non-human organism, such as a rat or mouse. Chimeras, CDR transplants and humanized antibodies are within the scope of the invention. Antibodies produced in non-human organisms, such as rats or mice, and then modified, for example, with variable frameworks or constant regions to reduce antigenicity in humans, are within the scope of the invention.

Chimeric antibodies can be produced by recombinant DNA technology known in the art (Robinson et al., International Patent Publication PCT / US86 / 02269; Akira, et al., European Patent Applications 184,187; Taniguchi, M., European Patent Application No. 171,496; Morrison et al., European Patent Application No. 173,494; Neuberger et al., International Application No. WO86 / 01533; Cabilly et al. , European Patent Application No. 125,023; Better et al. (1988 Science 240: 1041-1043); Liu et al. (1987) PNAS 84: 3439-3443; Liu et al., 1987, J. Immunol. 139: 3521-3526; Sun et al. (1987) PNAS 84: 214-218; Nishimura et al., 1987, Canc. Res. 47: 999-1005; Wood et al. (1985) Nature 314: 446-449; and See Shaw et al., 1988, J. Natl Cancer Inst. 80: 1553-1559).

Humanized or CDR-transplanted antibodies have at least one or two (of heavy and light immunoglobulin chains) replaced by donor CDRs, but generally all three recipient CDRs. The antibody may have at least part of the non-human CDRs replaced or some of the CDRs replaced with non-human CDRs. It is only essential to replace the number of CDRs required for binding of humanized antibodies to PD-1. Preferably, the donor is a rodent antibody, eg, a rat or mouse antibody, and the recipient is a human framework or a human consensus framework. Generally, the immunoglobulin that provides the CDR is referred to as the "donor" and the immunoglobulin that provides the framework is referred to as the "acceptor". In some embodiments, the donor immunoglobulin is non-human (eg, rodent). An acceptor framework is a naturally occurring (eg, human) framework or consensus framework or a sequence that is approximately 85% or more, preferably 90%, 95%, 99% or more identical to it.

As used herein, the term "consensus sequence" is a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see, eg, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987)). ). In a family of proteins, each position in the consensus sequence is occupied by the amino acids that most frequently appear at that position in the family. If the two amino acids appear at equal frequencies, either can be included in the consensus sequence. "Consensus framework" refers to the framework region of a consensus immunoglobulin sequence.

Antibodies can be humanized by methods known in the art (eg, Morrison, S. L., 1985, Science 229: 1202-1207, by Oi et al., 1986, all of which are incorporated herein by reference. , BioTechniques 4: 214 and Queen et al. US 5,585,089, US 5,693,761 and US 5,693,762).

Humanized or CDR transplanted antibodies can be produced by CDR transplantation or CDR substitution, where one, two or all CDRs of the immunoglobulin chain can be replaced. For example, US Pat. No. 5,225,539; Jones et al. 1986 Nature 321: 552-525; Verhoeyan et al. 1988 Science 239: 1534; Beidler et al. . 1988 J. Immunol. 141: 4053-4060; See Winter US 5,225,539. Winter describes a CDR transplantation method that can be used to produce the humanized antibody of the invention (UK patent application GB218638A filed March 26, 1987; Winter US 5,225,539), which is cited by reference. Explicitly included herein.

Also within the scope of the present invention are humanized antibodies in which specific amino acids have been substituted, deleted or added. Criteria for selecting amino acids from donors are described in US 5,585,089, eg, columns 12-16 of US 5,585,089, eg, columns 12-16 of US 5,585,089, which are described. , Incorporated herein by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP519596A1 published December 23, 1992.

The antibody molecule can be a single chain antibody. Single-chain antibodies (scFVs) may be modified (eg, Colcher, D. et al. (1999) Ann N Y Acad Sci 880: 263-80; and Reiter, Y. (1996) Clin Cancer Res 2: See 245-52). Single-chain antibodies can be dimerized or multimerized to produce multivalent antibodies with specificity for different epitopes of the same target protein.

In yet another embodiment, the antibody molecule is a heavy chain constant region of, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE; in particular, eg, IgG1, IgG2, IgG3 and IgG4 (eg, eg, IgG1, IgG2, IgG3 and IgG4). Human) Has a heavy chain constant region selected from the heavy chain constant region. In another embodiment, the antibody molecule has a light chain constant region selected from, for example, a kappa or lambda (eg, human) light chain constant region. The constant region can be modified, eg, mutated (eg, Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function and / or complement function) to modify the properties of the antibody. To increase or decrease). In some embodiments, the antibody has effector function and is capable of immobilizing complement. In other embodiments, the antibody does not collect effector cells or immobilize complement. In other embodiments, the antibody has reduced or no ability to bind to Fc receptors. For example, it has an isotype or subtype, fragment or other variant that does not support binding to the Fc receptor, eg, a mutagenesis or deleted Fc receptor binding region.

Methods of modifying antibody constant regions are known in the art. Antibodies with modified functions, eg, modified affinity for effector ligands such as the FcR of cells or the C1 component of complement, replace at least one amino acid residue in the constant portion of the antibody with a different residue. (See, for example, EP388,151A1, US Pat. No. 5,624,821 and US Pat. No. 5,648,260, the entire contents of which are incorporated herein by reference). Similar types of modifications can be described, which reduce or eliminate these functions if applied to mice or other species of immunoglobulins.

The antibody molecule can be derivatized or linked to other functional molecules (eg, other peptides or proteins). The "derivatized" antibody molecule used herein is one that has been modified. Derivatization methods include, but are not limited to, addition of fluorescent moieties, radionucleotides, toxins, enzymes or affinity ligands such as biotin. Accordingly, the antibody molecules of the invention are intended to include derivatized and other modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule is a protein capable of mediating the binding of another antibody (eg, a bispecific antibody or bispecific antibody), a detectable agent, a cytotoxic agent, a drug and / or an antibody or antibody moiety to another molecule. Alternatively, it may be functionally linked (chemically bound, gene fused, non-covalently associated or otherwise) to one or more other molecules such as a peptide (eg, streptavidin core region or polyhistidine tag).

One type of derivatized antibody molecule is produced by ligation of two or more antibodies (eg, of the same type or different types to make bispecific antibodies). Suitable crosslinkers are heterobifunctional (eg, m-maleimidebenzoyl-N-hydroxysuccinimide ester) or homobifunctional with two differently reactive groups separated by a suitable spacer. Includes (eg, dissuccinimidyl substrate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

The antibody molecule can be conjugated to other molecules, generally labeled or therapeutic (eg, cytotoxic or cell proliferation inhibitory) agents or moieties. Radioisotopes can be used in diagnostic or therapeutic applications. Radioisotopes capable of binding anti-PSMA antibodies include, but are not limited to, α-, β- or γ-emitters or β- and γ-emitters. Such radioactive isotopes include iodine ( ¹³¹ I or ¹²⁵ I), ittrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ Ac), placeodim, astatine ( ²¹¹ At), renium ( ¹⁸⁶ Re), bismuth. ( ²¹² Bi or ²¹³ Bi), Indium ( ¹¹¹ In), Lutetium ( ⁹⁹ mTc), Phosphorus ( ³² P), Rhodium ( ¹⁸⁸ Rh), Sulfur ( ³⁵ S), Carbon ( ¹⁴ C), Tritium ( ³ H), Includes, but is not limited to, chromium ( ⁵¹ Cr), chlorine ( ³⁶ Cl), cobalt ( ⁵⁷ Co or ⁵⁸ Co), iron ( ⁵⁹ Fe), selenium ( ⁷⁵ Se) or gallium ( ⁶⁷ Ga). Radioisotopes useful as therapeutic agents are ittrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ Ac), placeodium, astatine ( ²¹¹ At), renium ( ¹⁸⁶ Re), bismuth ( ²¹² Bi or ²¹³ Bi). And rhodium ( ¹⁸⁸ Rh). For example, radioisotopes useful as labels for diagnosis are iodine ( ¹³¹ I or ¹²⁵ I), indium ( ¹¹¹ In), technetium ( ⁹⁹ mTc), phosphorus ( ³² P), carbon ( ¹⁴ C) and Includes tritium ( ^3H ) or one or more of the therapeutic isotopes listed above.

The present invention provides radiolabeled antibody molecules and methods for labeling them. In certain embodiments, a method of labeling an antibody molecule is disclosed. The method comprises contacting an antibody molecule with a chelating agent, thereby producing a conjugated antibody. Conjugate antibodies are radiolabeled with radioisotopes such as ¹¹¹ indium, ⁹⁰ yttrium and ¹⁷⁷ lutetium to produce labeled antibody molecules.

As described above, the antibody molecule can be conjugated to a therapeutic agent. Therapeutic active radioisotopes have already been mentioned. Examples of other therapeutic agents are taxol, cytocaracin B, gramicidine D, ethidium bromide, emetin, mitomycin, etoposide, teniposide, vincristine, vinblastine, corhitin, doxorubicin, daunorubicin, dihydroxyanthracindione, mitoxantrone, mitoxantrone. , Actinomycin D, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, mitanorubicin, eg, mitanorubicin (see US Pat. No. 5,208,020), CC-1065 ( (See US Pat. No. 5,475,092, 5,585,499, 5,846,545) and analog or homologs thereof. Therapeutic agents include antimetabolites (eg, methotrexate, 6-mercaptopurine, 6-thioguanine, citaravin, 5-fluorouracildecarbazine), alkylating agents (eg, chlormethine, thioepachlorambusyl, CC-1065, melphalan). , Carmustine (BSNU) and Lomustine (CCNU), Cyclophosphamide, Busulfane, Dibromomannitol, Streptzotocin, Mitomycin C and cis-dichlorodiamine platinum (II) (DDP) cisplatin), Anthraculin (eg, daunorubicin (formerly daunorubicin) Daunorubicin) and doxorubicin), antibiotics (eg, dactinomycin (formerly actinomycin), bleomycin, mitramycin and anthramycin (AMC)) and anti-thread splitting agents (eg, vincristine, vinblastine, taxol and mytansinoid). ), But not limited to these.

Combination Therapies Combination therapies (eg, the methods and compositions described herein) include immunomodulators (eg, one or more activators of costimulatory molecules or inhibitors of immune checkpoint molecules) and second therapeutic agents, eg, It may include a second therapeutic agent selected from one or more of the agents listed in Table 1.

By "combination" or "combination" is not intended to mean that the therapeutic or multiple therapeutic agents are formulated for simultaneous application and / or delivery together (eg, the same composition), but these methods. And compositions are within the scope described herein. The immunomodulatory agent and the second therapeutic agent can be administered before or after at the same time as one or more other additional treatments or therapeutic agents. The agents in these combinations can be administered in any order. Generally, each drug is administered at the dose determined for that drug and / or on a time schedule. It is also further appreciated that additional therapeutic agents used in combination may be administered together as a single composition or separately as different compositions. In general, additional therapeutic agents used in combination are expected to be used individually at levels not exceeding the levels at which they are utilized. In some embodiments, the levels used in the combination are lower than those used herein.

In some embodiments, the combination comprises the formulation of an immunomodulatory agent and a second therapeutic agent with or without instructions regarding the combination use or combination product. The combined compounds may be manufactured and / or formulated by the same or different vendors. The combination partner can therefore be a completely different pharmaceutical dosage form or composition that is also sold independently of each other. In some embodiments, instructions for its combined use are (i) prior to being passed on to the physician (eg, in the case of a "kit" containing the disclosed compound and other therapeutic agent); (ii) immediately prior to administration by the physician (or or). Under the guidance of a physician); (iii) may be provided to the patient himself by a physician or healthcare professional.

Immunomodulators The combination therapies disclosed herein may include inhibitors of the inhibitory molecule of the immune checkpoint molecule. The term "immune checkpoint" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules act as a "brake" that effectively downregulates or inhibits the antitumor immune response. Inhibition of an inhibitory molecule can be performed by inhibition at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA or shRNA) can be used to inhibit the expression of the inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide that binds to the inhibitory molecule, such as a soluble ligand or antibody or antigen-binding fragment thereof.

Immune checkpoint molecules useful in the methods and compositions of the invention are Program Death 1 (PD-1), PD-1, PD-L1, PD-L2, Cytotoxicity T Lymphocyte Antigen 4 (CTLA-4), TIM-3, CEACAM (eg CEACAM-1, CEACAM-3 and / or CEACAM-5), LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H1, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC Class I, MHC Class II, GAL9, adenosine, TGFR (eg, TGFR beta), but not limited to these. In some embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule (eg, PD-1, PD-L1, LAG-3, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5). ) Or CTLA-4 or any combination of these inhibitors).

In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody selected from nivolumab, pembrolizumab or pidirizumab.

In some embodiments, the anti-PD-1 antibody is nivolumab. Other names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538 or BMS-936558. In some embodiments, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1. Other human monoclonal antibodies that specifically bind nivolumab (clone 5C4) and PD-1 are disclosed in US 8,008,449 and WO2006 / 121168. In some embodiments, the inhibitor of PD-1 is nivolumab, which is a sequence disclosed herein (or a sequence substantially identical or similar thereto, eg, at least 85%, 90%, 95% or it of a particular sequence. It has the same sequence).

The heavy and light chain amino acid sequences of nivolumab are as follows:
Heavy chain (SEQ ID NO: 2)
QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
Light chain (SEQ ID NO: 3)
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGLS

In some embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (also referred to as lambbrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US8,354,509 and WO2009 / 114335. Has been done. In certain embodiments, the inhibitor of PD-1 is disclosed, for example, in US8,354,509 and WO2009 / 114335, and the sequences disclosed herein (or sequences substantially identical or similar thereto, eg, specific sequences. Pembrolizumab having at least 85%, 90%, 95% or more identical sequences).
The heavy and light chain amino acid sequences of pembrolizumab are as follows:
Heavy chain (SEQ ID NO: 4)
QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG 50
INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD 100
YRFDMGFDYW GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT 200
YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT 250
LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQF N STY 300
RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT 350
LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400
DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447
Light chain (SEQ ID NO: 5)
EIVLTQSPAT LSLSPGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL 50
LIYLASYLES GVPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQHSRDLPL 100
TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150
QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200
THQGLSSPVT KSFNRGEC 218

In some embodiments, the anti-PD-1 antibody is pidirisumab. Pidirisumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD-1. Pidirisumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009 / 101611.

Other anti-PD-1 antibodies, among others, include AMP 514 (Amplimmune), an anti-PD-1 antibody disclosed in, for example, US8,609,089, US20100028330 and / or US20110114649. include.

Examples of PD-L1 or PD-L2 Inhibitors In certain embodiments, the PD-L1 inhibitor is an antibody molecule. In certain embodiments, the anti-PD-Ll inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105.

In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1. Pembrolizumab and other humanized anti-PD-L1 antibodies are disclosed in WO2013 / 079174, and the sequences disclosed herein (or sequences substantially identical or similar thereto, eg, at least 85%, 90 of the particular sequence). %, 95% or more identical sequences). The heavy and light chain amino acid sequences of MSB0010718C include at least:
Heavy chain variable region (SEQ ID NO: 24 disclosed in WO2013 / 079174) (SEQ ID NO: 6)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS
Light chain variable region (SEQ ID NO: 25 disclosed in WO2013 / 079174) (SEQ ID NO: 7)
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL

In some embodiments, the PD-L1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is the anti-PD-Ll (heavy and light chain variable region sequences set forth in SEQ ID NOs: 20 and 21, respectively of WO2010 / 077634) described in WO2010 / 077634 and is disclosed therein. It has a sequence (or a sequence that is substantially identical or similar to it, eg, a sequence that is at least 85%, 90%, 95% or more identical to the particular sequence).

In some embodiments, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-Ll antibody described in WO2007 / 005874, a sequence disclosed therein (or a sequence substantially identical or similar thereto, eg, specific. Has at least 85%, 90%, 95% or more identical sequences).

In some embodiments, the PD-L1 inhibitor is MDPL3280A (Genentech / Roche). MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds PD-L1. Other human monoclonal antibodies to MDPL3280A and PD-L1 are disclosed in US Pat. No. 7,943,743 and US Publication No. 20120039906.

In another embodiment, the PD-L2 inhibitor is AMP-224. AMP-224 is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD-1 and B7-H1 (B7-DCIg; Amplimmune; eg disclosed in WO2010 / 027827 and WO2011 / 066342).

Examples of TIM-3 Inhibitors In certain embodiments, the combinations described herein include TIM-3 inhibitors. In some embodiments, the combination is used to treat a cancer, eg, a cancer described herein, eg, a solid tumor or a hematological malignancy.

Examples of anti-TIM-3 antibodies are disclosed in US Pat. Nos. 8,552,156, WO2011 / 155607, EP2581113 and US Publication 2014/044728.

Examples of LAG-3 Inhibitors In certain embodiments, the combinations described herein comprise a LAG-3 inhibitor. In some embodiments, the combination is used to treat a cancer, eg, a cancer described herein, eg, a solid tumor or a hematological malignancy.

In some embodiments, the anti-LAG-3 antibody is BMS-986016. BMS-986016 (also referred to as BMS986016; Bristol-Myers Squibb) is a monoclonal antibody that binds to LAG-3. BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in US2011 / 0150892, WO2010 / 019570 and WO2014 / 0218.

Examples of CTLA-4 Inhibitors In certain embodiments, the combinations described herein include CTLA-4 inhibitors. In some embodiments, the combination is used to treat a cancer, eg, a cancer described herein, eg, a solid tumor or a hematological malignancy.

Examples of anti-CTLA-4 antibodies are tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and ipilimumab (CTLA-4 antibody, MDX-010, CAS No. 477202). Also known as -00-9).

In some embodiments, the combination comprises, for example, an anti-PD-1 antibody molecule and an anti-CTLA-4 antibody, such as ipilimumab, as described herein. Examples of doses that can be used include doses of about 1-10 mg / kg, eg, 3 mg / kg of anti-PD-1 antibody molecule and about 3 mg / kg of anti-CTLA-4 antibody, eg, ipilimumab. In some embodiments, the anti-PD-1 antibody molecule is treated after treatment, eg, after treatment of melanoma with an anti-CTLA-4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib). ,Administer

Other examples of anti-CTLA-4 antibodies are disclosed, for example, in US Pat. No. 5,811,097.

In some embodiments, the inhibitor is a soluble ligand (eg, CTLA-4-Ig) or antibody or antibody fragment that binds to PD-L1, PD-L2 or CTLA-4. For example, an anti-PD-1 antibody molecule may be administered in combination with an anti-CTLA-4 antibody, eg, ipilimumab, to, for example, cancer (eg, melanoma, eg, metastatic melanoma; lung cancer, eg, non-small cell lung cancer; Or cancer selected from prostate cancer) can be treated.

Further Combinations of Inhibitors In certain embodiments, the anti-PD-1 molecules disclosed herein are one or more other inhibitors of PD-1, PD-L1 and / or PD-L2, eg, as described herein. Administer in combination with. The antagonist can be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein or an oligopeptide.

In some embodiments, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof. In another embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with the anti-TIM-3 antibody or its antigen-binding fragment. In yet another embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with the anti-LAG-3 antibody and the anti-TIM-3 antibody or antigen-binding fragment thereof. The combinations of antibodies cited herein may be administered separately, eg, as separate antibodies, or as linked, eg, bispecific or trispecific antibody molecules. In certain embodiments, a bispecific antibody comprising an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody or an antigen-binding fragment thereof is administered. In certain embodiments, the combination of antibodies cited herein is used for the treatment of a cancer, eg, a cancer as described herein (eg, a solid tumor). The efficacy of the combination can be tested on animal models known in the art. For example, animal models for testing the synergistic effects of anti-PD-1 and anti-LAG-3 are described, for example, in Woo et al. (2012) Cancer Res. 72 (4): 917-27.

In other embodiments, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an inhibitor of CEACAM (eg, CEACAM-1, -3 and / or -5). In some embodiments, the inhibitor of CEACAM (eg, CEACAM-1, -3 and / or -5) is an anti-CEACAM antibody molecule. Without wishing to be bound by theory, carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1 and CEACAM-5 are thought to mediate, at least in part, inhibition of the antitumor immune response (eg, for example. Markel et al. J Immunol. 2002 Mar 15; 168 (6): 2803-10; Markel et al. J Immunol. 2006 Nov 1; 177 (9): 6062-71; Markel et al. Immunology. 2009 Feb; 126 (2): 186-200; Markel et al. Cancer Immunol Immunother. 2010 Feb; 59 (2): 215-30; Ortenberg et al. Mol Cancer Ther. 2012 Jun; 11 (6): 1300-10; Stern et al. J Immunol. 2005 Jun 1; 174 (11): 6692-701; Zheng et al. PLoS One. 2010 Sep 2; 5 (9). See pii: e12529). For example, CEACAM-1 has been described as a heterophyllic ligand for TIM-3 and as having a role in TIM-3 intervening T cell tolerance and depletion (eg, WO2014 / 022332; Huang, et al. (2014). ) Nature doi: 10.1038 / nature13848). In some embodiments, co-blocking of CEACAM-1 and TIM-3 has been shown to enhance the antitumor immune response in a xenograft colorectal cancer model (eg, WO2014 / 022332; Huang, et al. (Eg.). 2014), see supra). In another embodiment, co-blocking of CEACAM-1 and PD-1 reduces T cell tolerance, eg, as described in WO2014 / 059251. Therefore, CEACAM inhibitors can be used with other immunomodulators described herein (eg, anti-PD-1 and / or anti-TIM-3 inhibitors) to cancer, eg, melanoma, lung cancer (eg, eg, anti-PD-1 and / or anti-TIM-3 inhibitors). It can enhance the immune response against NSCLC), bladder cancer, colon cancer, ovarian cancer and other cancers as described herein.

Thus, in some embodiments, the anti-PD-1 antibody molecule is administered in combination with a CEACAM inhibitor (eg, a CEACAM-1, CEACAM-3 and / or a CEACAM-5 inhibitor). In some embodiments, the inhibitor of CEACAM is an anti-CEACAM antibody molecule. In some embodiments, the anti-PD-1 antibody molecule is administered in combination with a CEACAM-1 inhibitor, eg, an anti-CEACAM-1 antibody molecule. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a CEACAM-3 inhibitor, eg, an anti-CEACAM-3 antibody molecule. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a CEACAM-5 inhibitor, eg, an anti-CEACAM-5 antibody molecule. Examples of anti-CEACAM-1 antibodies are disclosed in WO2010 / 125571, WO2013 / 082366 and WO2014 / 022332, eg, monoclonal antibodies 34B1, 26H7 and 5F4; or, for example, US2004 / 0047858, US7,132,255. It is a recombinant form from it as described in No. and WO99 / 052552. In other embodiments, the anti-CEACAM antibody is described in, for example, Zheng et al. PLoS One. 2010 Sep 2; 5 (9). Pii: e12529 (DOI: 10: 1371 / journal.pone.0021146). It binds to -5 or cross-reacts with CEACAM-1 and CEACAM-5, for example, as described in WO2013 / 054331 and US2014 / 0271618.

Co-stimulatory Modulators In certain embodiments, the combination therapies disclosed herein include modulators of co-stimulatory molecules. In some embodiments, the agonist of a costimulatory modulator, eg, a costimulatory molecule, is an MHC class I molecule, a TNF receptor protein, an immunoglobulin-like protein, a cytokine receptor, an integrin, a signaling lymphatic activation molecule (SLAM protein). ), Activated NK cell receptor, BTLA, Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a / CD18), 4-1BB (CD137) ), B7-H3, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHT), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2Rgamma, IL7R Alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, IT , ITGB7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PS SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), SLAM7, BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG / Cbp , A agonist of a ligand that specifically binds to CD19a and CD83 (eg, an agonist antibody or an antigen-binding fragment thereof or a soluble fusion).

In certain embodiments, the combination therapies disclosed herein include agonists associated with positive signals, including the co-stimulatory molecules, eg, the co-stimulatory domains of CD28, CD27, ICOS and GITR.

Examples of GITR Agonists In certain embodiments, the combinations described herein include GITR agonists. In some embodiments, the combination is used to treat a cancer, eg, a cancer described herein, eg, a solid tumor or a hematological malignancy.

Examples of GITR agonists are, for example, the GITR fusion proteins described in US Pat. No. 6,111,090, European Patent No. 0920505B1, US Pat. No. 8,586,023, PCT Publications WO2010 / 00318 and 2011/090754 or, for example. US Patent 7,025,962, European Patent 1947183B1, US Patent 7,812,135, US Patent 8,388,967, US Patent 8,591,886, European Patent EP18663339, PCT Publication WO2011 / 028683, US Patent 8,709,424, PCT Publication WO2013 / 039954, International Publication WO2013 / 039554, US Publication US2014 / 0072566, International Publication WO2015 / 026684, PCT Publication WO2005 / 07190, PCT Publication WO2007 / 133822, PCT published WO2005 / 055808, PCT published WO99 / 40196, PCT published WO2001 / 03720, PCT published WO99 / 20758, US patent 6,689,607, PCT published WO2006 / 083289, PCT published GITR fusion proteins and anti-GITR antibodies, such as the anti-GITR antibodies described in WO2005 / 115451, US Pat. Bivalent anti-GITR antibody) is included.

In certain embodiments, the GITR agonist is used in combination with a TLR agonist, eg, as described in WO2015 / 026684.

In other embodiments, the GITR agonist is used in combination with a TLR agonist, eg, as described in WO200460319 and WO20140124979.

Further Combinations In other embodiments, combination therapy comprises a combination with adopted T cell immunotherapy using modified T cells, eg, chimeric antigen receptor (CAR) T cells (eg, John LB, et al. (2013). ) Clin. Cancer Res. 19 (20): as described by 5636-46).

In other embodiments, the combination therapies disclosed herein may also include cytokines such as interleukin-21 or interleukin-2. In certain embodiments, the combinations described herein are used to treat a cancer, eg, a cancer as described herein (eg, solid tumor or melanoma).

Examples of immunomodulators that can be used in combination therapy include, for example, aftuzumab (available from Roche®); pegfilgrastim (Neulasta®); renalidemide (CC-5013, Revlimid®). Salidomide (Salomid®), Actimid (CC4047); and human cytokine mixture containing cytokines such as IL-21 or IRX-2 (interleukin 1, interleukin 2 and interferon gamma, CAS 951209-71-5). , Available from IRX Therapeutics).

In other embodiments, the combination therapy is such as bone marrow transplantation, T cell ablation therapy using chemotherapeutic agents such as fludarabine, external beam radiotherapy (XRT), cyclophosphamide and / or OKT3 or campus. Administer with one or more of the antibodies (eg, before, at the same time, or after). In some embodiments, the anti-PD-1 or PD-L1 antibody molecule is administered after B cell ablation therapy, such as a drug that reacts with CD20, eg, Rituxan. For example, in some embodiments, the subject may receive standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In some embodiments, after transplantation, the subject receives an anti-PD-1 or PD-L1 antibody molecule. In a further embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered before or after surgery.

Other examples of additional combination therapies include decarbazine for the treatment of melanoma. Without being bound by theory, the combined use of PD-1 blockade and chemotherapeutic is promoted by cell death, which is the result of the cytotoxic effects of most chemotherapeutic compounds that can result in increased tumor antigen levels in the antigen presenting pathway. It is thought that it will be done. Other combination therapies that can synergize with PD-1 blockade by cell death are radiation, surgery and hormone deficiency. Each of these protocols forms a source of tumor antigen in the host. Angiogenesis inhibitors can also be combined with PD-1 blockade. Inhibition of angiogenesis leads to tumor cell death, which can supply tumor antigen to the host antigen presentation pathway.

Combination therapy can also be used in combination with bispecific antibodies. Bispecific antibodies can be used to target two separate antigens. For example, anti-Fc receptor / anti-tumor antigen (eg, Her-2 / neu) bispecific antibodies have been used to target macrophages to the site of the tumor. This targeting efficiently activates tumor-specific responses. The T cell arm of these responses is enhanced by the use of PD-1 blockade. Alternatively, the antigen may be delivered directly to the DC by the use of a bispecific antibody that binds to a tumor antigen and a dendritic cell-specific cell surface marker.

Tumors escape host immune surveillance by a wide variety of mechanisms. Many of these mechanisms are expressed by tumors and can be defeated by inactivation of immunosuppressive proteins. These are, among other things, TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992)). Immunology Today 13: 198-200) and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363-1365) are included. Antibodies to each of these or antigen-binding fragments thereof are used in combination with anti-PD-1 to disrupt the action of immunosuppressive factors and support the tumor immune response by the host.

Other antibodies that can be used to activate host immune reactivity can be used in combination with the combination therapies described herein. These include surface molecules of dendritic cells that activate DC function and antigen presentation. Anti-CD40 antibody can efficiently replace T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in combination with PD-1 antibody (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40). CTLA-4 (eg, US Pat. No. 5,811,097), OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al. (1997)) Antibodies to T cell costimulatory molecules, such as Nature Medicine 3: 682-685 (1997) and ICOS (Hutloff, A. et al. (1999) Nature 397: 262-266), are also at T cell activation levels. May be offered for an increase in.

In all of the methods described herein, PD-1 blockade is a cytokine treatment (eg, interferon, GM-CSF, G-CSF, IL-2, IL-21) or bispecific that provides enhanced tumor antigen presentation. It can be combined with other forms of immunotherapy such as target antibody therapy (see, eg, Holliger (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448; Poljak (1994) Structure 2: 1121-1123).

The combination therapy disclosed herein can be further combined with immunogens such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells into which genes encoding immunostimulatory cytokines have been introduced. Can be combined (He et al. (2004) J. Immunol. 173: 4919-28). Non-limiting examples of tumor vaccines available are those of melanoma antigens, such as tumor cell peptides gene-introduced to express gp100, MAGE antigen, Trp-2, MART1 and / or tyrosinase or cytokine GM-CSF. Contains peptides.

PD-1 blockade can be combined with the vaccination protocol. Many experimental strategies for vaccination against tumors have been devised (Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300. -302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. See Fifth Edition). In one of these strategies, vaccines are manufactured using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43).

PD-1 blockade can be used in combination with a collection of recombinant proteins and / or peptides expressed in tumors to produce an immune response against these proteins. These proteins are usually found as self-antigens in the immune system and are therefore acceptable to them. Tumor antigens can also include protein telomerase, which is required for chromosomal telomere synthesis and is expressed in over 85% of human cancers and only in limited somatic tissues (Kim, N et al. (1994)). Science 266: 2011-2013). (These somatic tissues can be protected from immune attack by various means). Tumor antigens also alter protein sequences or make fusion proteins between two unrelated sequences (ie, bcr-abl on the Philadelphia chromosome) somatic mutations that are expressed in cancer cells as "neoantigens" or B. It can also be an idiotype from a cell tumor.

Other tumor vaccines may include proteins from viruses associated with human cancer such as human papillomavirus (HPV), hepatitis virus (HBV and HCV) and Kaposi herpes sarcoma virus (KHSV). Another form of tumor-specific antigen that can be used in combination with PD-1 blockade is purified heat shock protein (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of the protein from tumor cells, and these HSPs are highly effective in delivering antigen-presenting cells to elicit tumor immunity (Suot, R & Srivastava, P (1995). ) Science 269: 1585-1588; Tamura, Y. et al. (1997) Science 278: 117-120).

Dendritic cells (DCs) are potent antigen-presenting cells that can be used to trigger antigen-specific responses. DCs are produced in Exvivo and can be loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DC can also be transduced by genetic means to express these tumor antigens as well. DC has also been directly fused to tumor cells for immunization purposes (Kugler, A. et al. (2000) Nature Medicine 6: 332-336). As a method of vaccination, DC immunization can be efficiently combined with PD-1 blockade to activate a stronger antitumor response.

Second therapeutic agent The second therapeutic agent is 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) histon deacetylase. (HDAC) Inhibitors; 7) Janus Kinase Inhibitors; 8) FGF Receptor Inhibitors; 9) EGF Receptor Inhibitors; 10) c-MET Inhibitors; 11) ALK Inhibitors; 12) CDK4 / 6 Inhibitors 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CAR T cells that target CD19); 16) MEK inhibitors; or 17) BCR-ABL inhibitors selected from 1 The above; for example, it may be one or more drugs listed in Table 1.

Examples of Combination Therapies In certain embodiments, inhibitors of immune checkpoint molecules are used in the methods or compositions described herein. For example, an inhibitor of the immunocheckpoint molecule described herein, eg, a PD-1 inhibitor, eg, an anti-PD-1 antibody (eg, nibolumab or penbrolizumab); or a PD-L1 inhibitor, eg, an anti-PD-L1. An antibody (eg, MSB0010718C) (alone or in combination with other immunomodulators) is one or more agents listed in Table 1; eg, 1) an inhibitor of an apoptosis (IAP) inhibitor; 2) a rapamycin (TOR). ) Kinase-targeted inhibitors; 3) Mouse double microchromatoid 2 E3 ubiquitin ligase human homologue (HDM2) inhibitors; 4) PIM kinase inhibitors; 5) Human epidermal growth factor 3 (HER3) kinase inhibitors; 6) Histon deacetylase (HDAC) inhibitor; 7) Janus kinase inhibitor; 8) Fibroblast growth factor receptor (FGF) receptor inhibitor; 9) Epidermal growth factor (EGF) receptor inhibitor; 10) c-MET inhibitors; 11) ALK inhibitors; 12) CDK4 / 6 inhibitors; 13) PI3K inhibitors; 14) BRAF inhibitors; 15) CAR T cells (eg, CAR T cells that target CD19). ); 16) MEK inhibitor or 17) BCR-ABL inhibitor. In some embodiments, one or more of the above combinations is used to treat a disorder, eg, a disorder described herein (eg, a disorder disclosed in Table 1). In some embodiments, one or more of the above combinations is used to treat a cancer, eg, a cancer described herein (eg, a cancer disclosed in Table 1).

In certain embodiments, one or more of the immunomodulators described herein are used in combination with:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or 8) 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide.

Each of these combinations is described in more detail below.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an IAP inhibitor to use a cancer, eg, a cancer described herein (eg, in Table 1). Disclose cancer) to treat. In some embodiments, IAP inhibitors are disclosed in Table 1, eg, LCL161 or publications cited in Table 1, eg, International Patent Publication WO 2008/016893 (eg, Formula (I), Example 1 and Compound A). ), European Patent No. 2051990 and US Pat. No. 8,546,336. In some embodiments, IAP inhibitors are disclosed, for example, in International Patent Publication WO 2008/016893 (eg, Formula (I), Example 1 and Compound A), European Patent 2051990 and US Pat. No. 8,546,336. To. In some embodiments, the IAP inhibitor, eg, LCL161, is a publication provided in Table 1 or cited in Table 1, eg, International Patent Publication WO 2008/016893 (eg, Formula (I), Example 1 and Compound A). , European Patent 2051990 and US Pat. No. 8,546,336 having a structure (compound or general). In certain embodiments, an inhibitor of an immune checkpoint molecule (eg, nibolumab, pembrolizumab or one of MSB0010718C) is used in combination with LCL161 for the cancers or disorders listed in Table 1, eg, solid tumors, eg, breast cancer or. Treat pancreatic cancer; or hematopoietic tumors, such as multiple myeloma or hematopoietic disorders.

〔式中、Ｒ_１はＨ、Ｃ_１－Ｃ_４アルキル、Ｃ_２－Ｃ_４アルケニル、Ｃ_２－Ｃ_４アルキニルまたはＣ_３－Ｃ_１０シクロアルキルであり、該Ｒ_１は置換されていなくてもされていてもよく；
Ｒ_２はＨ、Ｃ_１－Ｃ_４アルキル、Ｃ_２－Ｃ_４アルケニル、Ｃ_２－Ｃ_４アルキニル、Ｃ_３－Ｃ_１０シクロアルキルであり、該Ｒ_２は置換されていなくてもされていてもよく；
Ｒ_３はＨ、ＣＦ_３、Ｃ_２Ｆ_６、Ｃ_１－Ｃ_４アルキル、Ｃ_２－Ｃ_４アルケニル、Ｃ_２－Ｃ_４アルキニル、ＣＨ_２－Ｚであるかまたは
Ｒ_２およびＲ_３は、それらが結合している窒素原子と一体となって、ヘテロ環式環を形成し、該アルキル、アルケニル、アルキニルまたはｈｅｔ環は置換されていなくてもされていてもよく；
ＺはＨ、ＯＨ、Ｆ、Ｃｌ、ＣＨ_３、ＣＨ_２ＣＩ、ＣＨ_２ＦまたはＣＨ_２ＯＨであり；
Ｒ_４はＣ_０－１０アルキル、Ｃ_０－１０アルケニル、Ｃ_０－１０アルキニル、Ｃ_３－Ｃ_１０シクロアルキルであり、ここで、Ｃ_０－１０アルキルまたはシクロアルキル基は置換されていないかまたは置換されており；
Ａはｈｅｔであり、これは、置換されていてもされていなくてもよく；
ＤはＣ_１－Ｃ_７アルキレンまたはＣ_２－Ｃ_９アルケニレン、Ｃ(Ｏ)、Ｏ、ＮＲ_７、Ｓ(Ｏ)ｒ、Ｃ(Ｏ)－Ｃ_１－Ｃ_１０アルキル、０－Ｃ_１－Ｃ_１０アルキル、Ｓ(Ｏ)ｒ－Ｃ_ｒＣ_１０アルキル、Ｃ(Ｏ)Ｃ_０－Ｃ_１０アリールアルキル、ＯＣ_０－Ｃ_１０アリールアルキルまたはＳ(Ｏ)ｒＣ_０－Ｃ_１０アリールアルキルであり、該アルキル基およびアリール基は置換されていなくてもされていてもよく；
ｒは０、１または２であり；
Ａ_１は、置換または非置換アリールまたは非置換または置換ｈｅｔであり、アリールおよびｈｅｔの置換基は、ハロ、アルキル、低級アルコキシ、ＮＲ_５Ｒ_６、ＣＮ、ＮＯ_２またはＳＲ_５であり；
各Ｑは、独立して、Ｈ、Ｃ_１－Ｃ_１０アルキル、Ｃ_１－Ｃ_１０アルコキシ、アリールＣ_１－Ｃ_１０アルコキシ、ＯＨ、Ｏ－Ｃ_１－Ｃ_１０アルキル、(ＣＨ_２)_０－６－Ｃ_３－Ｃ_７シクロアルキル、アリール、アリールＣ_１－Ｃ_１０アルキル、Ｏ－(ＣＨ_２)_０－６アリール、(ＣＨ_２)_１－_６ｈｅｔ、ｈｅｔ、Ｏ－(ＣＨ_２)_１－６ｈｅｔ、－ＯＲ_１１、Ｃ(Ｏ)Ｒ_１１、－Ｃ(Ｏ)Ｎ(Ｒ_１１)(Ｒ_１２)、Ｎ(Ｒ_１１)(Ｒ_１２Ｊ_１ＳＲ_１１、Ｓ(Ｏ)Ｒ_１１１Ｓ(Ｏ)_２Ｒ_１１、Ｓ(Ｏ)_２－Ｎ(Ｒ_１１)(Ｒ_１２)またはＮＲ_１１－Ｓ(Ｏ)_２－(Ｒ_１２)であり、ここで、アルキル、シクロアルキルおよびアリールは置換されていないかまたは置換されており；
ｎは０、１、２または３、４、５、６または７であり；
ｈｅｔは、Ｎ、ＯおよびＳから選択される１～４ヘテロ環原子を含む５～７員単環式ヘテロ環式環またはＮ、ＯおよびＳから選択される１、２または３ヘテロ環原子を含む１つの５～７員単環式ヘテロ環式環を含む８～１２員縮合環系であり、該ｈｅｔは置換されていないかまたは置換されており；
Ｒ_１１およびＲ_１２は、独立して、Ｈ、Ｃ_１－Ｃ_１０アルキル、(ＣＨ_２)_０－６－Ｃ_３－Ｃ_７シクロアルキル、(ＣＨ_２)_０－６－(ＣＨ)_０－１(アリール)_１._２,Ｃ(Ｏ)－Ｃ_１－Ｃ_１０アルキル、－Ｃ(Ｏ)－(ＣＨ_２)_１－６－Ｃ_３－Ｃ_７シクロアルキル、－Ｃ(Ｏ)－Ｏ－(ＣＨ_２)_０－６－アリール、－Ｃ(Ｏ)－(ＣＨ_２)_０－６－Ｏ－フルオレニル、Ｃ(Ｏ)－ＮＨ－(ＣＨ_２)_０－６－アリール、Ｃ(Ｏ)－(ＣＨ_２)_０－６－アリール、Ｃ(Ｏ)－(ＣＨ_２)_１－６－ｈｅｔ、－Ｃ(Ｓ)－Ｃ_ｒＣ_１０アルキル、－Ｃ(Ｓ)－(ＣＨ_２)_Ｌ６－Ｃ_３－Ｃ_７シクロアルキル、－Ｃ(Ｓ)－Ｏ－(ＣＨ_２Ｗアリール、－Ｃ(Ｓ)－(ＣＨ_２)_０－６－Ｏ－フルオレニル、Ｃ(Ｓ)－ＮＨ－(ＣＨ_２)_０－６－アリール、－Ｃ(Ｓ)－(ＣＨ_２)_０－６－アリールまたはＣ(Ｓ)－(ＣＨ_２)_１－６－ｈｅｔ、Ｃ(Ｏ)Ｒ_１１、Ｃ(Ｏ)ＮＲ_１１Ｒ_１２、Ｃ(Ｏ)ＯＲ_１１、Ｓ(Ｏ)_ｎＲ_１１、Ｓ(Ｏ)_１ｎＮＲ_１１Ｒ_１２、ｍ＝１または２、Ｃ(Ｓ)Ｒ_１１、Ｃ(Ｓ)ＮＲ_１１Ｒ_１２、Ｃ(Ｓ)ＯＲ_１１であり、ここで、アルキル、シクロアルキルおよびアリールは置換されていないかまたは置換されており；またはＲ_１１およびＲ_１２は、分子の細胞膜を超える輸送を促進する置換基であり、
またはＲ_１１およびＲ_１２は、窒素原子と一体となってｈｅｔを形成し
ここで、Ｒ_１１およびＲ_１２のアルキル置換基はＣ_１－Ｃ_１０アルキル、ハロゲン、ＯＨ、Ｏ－Ｃ_１－Ｃ_６アルキル、－Ｓ－Ｃ_１－Ｃ_６アルキル、ＣＦ_３またはＮＲ_１１Ｒ_１２から選択される１以上の置換基で置換されていなくてもされていてもよく；
Ｒ_１１およびＲ_１２の置換シクロアルキル置換基は、Ｃ_２－Ｃ_１０アルケン；Ｃ_１－Ｃ_６アルキル；ハロゲン；ＯＨ；Ｏ－Ｃ_１－Ｃ_６アルキル；Ｓ－Ｃ_１－Ｃ_６アルキル、ＣＦ_３；またはＮＲ_１１Ｒ_１２から選択される以上の置換基で置換されており；
Ｒ_１１およびＲ_１２の置換ｈｅｔまたは置換アリールは、ハロゲン、ヒドロキシ、Ｃ_１－Ｃ_４アルキル、Ｃ_１－Ｃ_４アルコキシ、ニトロ、ＣＮＯ－Ｃ(Ｏ)－Ｃ_ｒＣ_４アルキルおよびＣ(Ｏ)－Ｏ－Ｃ_ｒＣ_４－アルキルから選択される１以上の置換基で置換されており；
Ｒ_５、Ｒ_６およびＲ_７は、独立して水素、低級アルキル、アリール、アリール低級アルキル、シクロアルキルまたはシクロアルキル低級アルキル、Ｃ(Ｏ)Ｒ_５；Ｓ(Ｏ)Ｒ_５Ｃ(Ｏ)ＯＲ_５Ｃ(Ｏ)ＮＲ_５Ｒ_６であり、
Ｒ_１基、Ｒ_２基、Ｒ_３基、Ｒ_４基、Ｑ基およびＡ基およびＡ_１基の置換基は、独立してハロ、ヒドロキシ、低級アルキル、低級アルケニル、低級アルキニル、低級アルカノイル、低級アルコキシ、アリール、アリール低級アルキル、アミノ、アミノ低級アルキル、ジ低級アルキルアミノ、低級アルカノイル、アミノ低級アルコキシ、ニトロ、シアノ、シアノ低級アルキル、カルボキシ、低級カルボアルコキシ、低級アルカノイル、アリーロイル、低級アリールアルカノイル、カルバモイル、Ｎ－モノ－またはＮ,Ｎ－ジ低級アルキルカルバモイル、低級アルキルカルバミン酸エステル、アミジノ、グアニジン、ウレイド、メルカプト、スルホ、低級アルキルチオ、スルホアミノ、スルホンアミド、ベンゾスルホンアミド、スルホネート、スルファニル低級アルキル、アリールスルホンアミド、ハロゲン置換アリールスルホネート、低級アルキルスルフィニル、アリールスルフィニル；アリール－低級アルキルスルフィニル、低級アルキルアリールスルフィニル、低級アルキルスルホニル、アリールスルホニル、アリール－低級アルキルスルホニル、低級アリールアルキル低級アルキルアリールスルホニル、ハロゲン－低級アルキルメルカプト、ハロゲン－低級アルキルスルホニル、ホスホノ(－Ｐ(＝Ｏ)(ＯＨ)_２)、ヒドロキシ－低級アルコキシホスホリルまたはジ－低級アルコキシホスホリル、(Ｒ_９)ＮＣ(Ｏ)－ＮＲ_１０Ｒ_１３、低級アルキルカルバミン酸エステルまたはカルバメートまたは－ＮＲ_８Ｒ_１４であり、ここで、
Ｒ_８およびＲ_１４は同一でも異なってもよく、独立してＨまたは低級アルキルであるかまたは
Ｒ_８およびＲ_１４は、Ｎ原子と一体となって、１窒素ヘテロ環原子含有３～８員ヘテロ環式環を形成し、所望により、１または２の窒素、酸素および硫黄から選択されるさらなるヘテロ環原子を含んでいてよく、該ヘテロ環式環は低級アルキル、ハロ、低級アルケニル、低級アルキニル、ヒドロキシ、低級アルコキシ、ニトロ、アミノ、低級アルキル、アミノ、ジ低級アルキルアミノ、シアノ、カルボキシ、低級カルボアルコキシ、ホルミル、低級アルカノイル、オキソ、カルバモイル、Ｎ－低級またはＮ,Ｎ－ジ低級アルキルカルバモイル、メルカプトまたは低級アルキルチオで置換されていなくてもされていてもよく；
Ｒ_９、Ｒ_１０およびＲ_１３は、独立して水素、低級アルキル、ハロゲン置換低級アルキル、アリール、アリール低級アルキル、ハロゲン置換アリール、ハロゲン置換アリール低級アルキルである。〕
の化合物またはその薬学的に許容される塩である。 In some embodiments, the IAP inhibitor is the formula (I).

[In the formula, R ₁ is H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or C ₃ -C ₁₀ cycloalkyl, even if R ₁ is not substituted. May have been;
R ₂ is H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₁₀ cycloalkyl, even if R ₂ is substituted or substituted. Often;
R ₃ is H, CF ₃ , C ₂ F ₆ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, CH ₂ -Z or R ₂ and R ₃ are them. Together with the attached nitrogen atom to form a heterocyclic ring, the alkyl, alkenyl, alkynyl or het ring may or may not be substituted;
Z is H, OH, F, Cl, CH ₃ , CH ₂ CI, CH ₂ F or CH ₂ OH;
_R4 is C _0-10 alkyl, C _0-10 alkenyl, C _0-10 alkynyl, C ₃ -C ₁₀ cycloalkyl, where the C _0-10 alkyl or cycloalkyl group is not substituted or substituted. Has been replaced;
A is het, which may or may not be substituted;
D is C ₁ -C ₇ alkylene or C ₂ -C ₉ alkaneylene, C (O), O, NR ₇ , S (O) r, C (O) -C ₁ -C ₁₀ alkyl, 0-C ₁ -C ₁₀ Alkyl, S (O) r-C _r C ₁₀ Alkyl, C (O) C ₀ -C ₁₀ Aryl Alkyl, OC ₀ -C ₁₀ Aryl Alkyl or S (O) rC ₀ -C ₁₀ Aryl Alkyl. Alkyl and aryl groups may or may not be substituted;
r is 0, 1 or 2;
A ₁ is a substituted or unsubstituted aryl or unsubstituted or substituted het, and the substituents of the aryl and het are halo, alkyl, lower alkoxy, NR ₅ R ₆ , CN, NO ₂ or SR ₅ ;
Each Q is independently H, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, aryl C ₁ -C ₁₀ alkoxy, OH, OC ₁ -C ₁₀ alkyl, (CH ₂ ) _0-6 . -C ₃ -C ₇ cycloalkyl, aryl, aryl C ₁ -C ₁₀ alkyl, O- (CH ₂ ) _{0-6 aryl} , (CH ₂ ) _1-6 het, het, O- (CH ₂ ) _1-6 het, -OR ₁₁ , C (O) R ₁₁ , -C (O) N (R ₁₁ ) (R ₁₂ ), N (R ₁₁ ) (R ₁₂ J ₁ SR ₁₁ , S (O) R ₁₁₁ S (O) ) ₂ R ₁₁ , S (O) ₂ -N (R ₁₁ ) (R ₁₂ ) or NR ₁₁ -S (O) _2- (R ₁₂ ), where alkyl, cycloalkyl and aryl are substituted. Not or replaced;
n is 0, 1, 2 or 3, 4, 5, 6 or 7;
het is a 5- to 7-membered monocyclic heterocyclic ring containing 1 to 4 heterocyclic atoms selected from N, O and S or a 1, 2 or 3 heterocyclic atom selected from N, O and S. An 8- to 12-membered fused ring system comprising one 5- to 7-membered monocyclic heterocyclic ring comprising, the het being substituted or substituted;
R ₁₁ and R ₁₂ are independently H, C ₁ -C ₁₀ alkyl, (CH ₂ ) _0-6 -C ₃ -C ₇ cycloalkyl, (CH ₂ ) _0-6- (CH) _0-1 . (Aryl) _1.2 , C (O) -C _{1 -} C ₁₀ alkyl, -C (O)-(CH ₂ ) _1-6 -C ₃ -C ₇ cycloalkyl, -C (O) -O- ( CH ₂ ) _0-6 -aryl, -C (O)-(CH ₂ ) _0-6 -O-fluorenyl, C (O) -NH- (CH ₂ ) _0-6 -aryl, C (O)-( CH ₂ ) _0-6 -aryl, C (O)-(CH ₂ ) _1-6 -het, -C (S) _-Cr C ₁₀ alkyl, -C (S)-(CH ₂ ) _L6 -C ₃ -C ₇ cycloalkyl, -C (S) -O- (CH ₂ Waryl, -C (S)-(CH ₂ ) _0-6 -O-fluorenyl, C (S) -NH- (CH ₂ ) _{0 -6} -aryl, -C (S)-(CH ₂ ) _0-6 -aryl or C (S)-(CH ₂ ) _1-6 -het, C (O) R ₁₁ , C (O) NR ₁₁ R ₁₂ , C (O) OR ₁₁ , S (O) _n R ₁₁ , S (O) _1n NR ₁₁ R ₁₂ , m = 1 or 2, C (S) R ₁₁ , C (S) NR ₁₁ R ₁₂ , C (S) OR ₁₁ where alkyl, cycloalkyl and aryl are substituted or substituted; or R ₁₁ and R ₁₂ are substituents that facilitate transport of the molecule across the cell membrane. ,
Alternatively, R ₁₁ and R ₁₂ form a het integrally with the nitrogen atom, where the alkyl substituents of R ₁₁ and R ₁₂ are C ₁ -C ₁₀ alkyl, halogen, OH, OC ₁ -C ₆ It may or may not be substituted with one or more substituents selected from alkyl, -SC ₁ -C ₆ alkyl, CF ₃ or NR ₁₁ R ₁₂ ;
Substituent cycloalkyl substituents for R ₁₁ and R ₁₂ are C2 _- C ₁₀ alkenes; C ₁ -C ₆ alkyl; halogens; OH; OC ₁ -C ₆ alkyl; SC ₁ -C ₆ alkyl, CF. ₃ ; or substituted with more than or more substituents selected from NR ₁₁ R ₁₂ ;
Substituted hets or substituted aryls for R ₁₁ and R ₁₂ are halogen, hydroxy, C1- _C4 alkyl, C1- _C4 alkoxy, nitro, CNO _- C (O) _{-CrC 4} alkyl and C ₍ O). -OC _r C ₄ -substituted with one or more substituents selected from alkyl;
R ₅ , R ₆ and R ₇ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, cycloalkyl or cycloalkyl lower alkyl, C (O) R ₅ ; S (O) R ₅ C (O) OR. ₅ C (O) NR ₅ R ₆
The substituents of R ₁ , R ₂ , R ₃ , R 4, R ₄ , Q and A and A ₁ are independently halo, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower. Alkoxy, aryl, aryl lower alkyl, amino, amino lower alkyl, dilower alkylamino, lower alkanoyl, amino lower alkoxy, nitro, cyano, cyano lower alkyl, carboxy, lower carboalkoxy, lower alkanoyl, allyloyl, lower aryl alkanoyl, carbamoyl. , N-mono- or N, N-di lower alkylcarbamoyl, lower alkylcarbamic acid ester, amidino, guanidine, ureido, mercapto, sulfo, lower alkylthio, sulfoamino, sulfonamide, benzosulfonamide, sulfonate, sulfanyl lower alkyl, aryl Sulphonamide, halogen-substituted arylsulfonates, lower alkylsulfinyl, arylsulfinyl; aryl-lower alkylsulfinyl, lower alkylarylsulfinyl, lower alkylsulfonyls, arylsulfonyls, aryl-lower alkylsulfonyls, lower arylalkyl lower alkylarylsulfonyls, halogen-lower Alkyl mercapto, halogen-lower alkylsulfonyl, phosphono (-P (= O) (OH) ₂ ), hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, (R ₉ ) NC (O) -NR ₁₀ R ₁₃ , lower Alkyl carbamate or carbamate or -NR ₈ R ₁₄ , where,
R ₈ and R ₁₄ may be the same or different and are independently H or lower alkyl, or R ₈ and R ₁₄ are integrated with the N atom and are 3- to 8-membered hetero containing 1 nitrogen heterocycle atom. It may form a cyclic ring and optionally contain additional heterocyclic atoms selected from 1 or 2 nitrogen, oxygen and sulfur, the heterocyclic ring being a lower alkyl, halo, lower alkenyl, lower alkynyl, Hydroxy, lower alkoxy, nitro, amino, lower alkyl, amino, di-lower alkylamino, cyano, carboxy, lower carboalkoxy, formyl, lower alkanoyl, oxo, carbamoyl, N-lower or N, N-di lower alkyl carbamoyl, mercapto Alternatively, it may or may not be substituted with a lower alkylthio;
R ₉ , R ₁₀ and R ₁₃ are independently hydrogen, lower alkyl, halogen-substituted lower alkyl, aryl, aryl lower alkyl, halogen-substituted aryl, halogen-substituted aryl lower alkyl. ]
Compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the LCL161 has the following structure:

In some embodiments, the LCL161 comprises (S) -N-((S) -1-cyclohexyl-2-((S) -2-(4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl). )-2-oxoethyl) -2- (methylamino) propanamide.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a TOR kinase inhibitor to use a cancer, eg, a cancer described herein (eg, a table). The cancer disclosed in 1) is treated. In some embodiments, TOR kinase inhibitors are disclosed in Table 1 (eg, Rad-001) or publications cited in Table 1, eg, International Patent Publication WO2014 / 085318 (eg, Compound B). In some embodiments, a TOR kinase inhibitor, such as Rad-001, is described, for example, in the publications provided in Table 1 or cited in Table 1, eg, International Patent Publication WO2014 / 085318 (eg, Compound B). Has a structure (compound or general structure). In certain embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, penbrolizumab or one of MSB0010718C) is used in combination with Rad-001 for the cancers or disorders listed in Table 1, eg, solid tumors, eg, solid tumors. , Sarcoma, lung cancer (eg, non-small cell lung cancer (NSCLC) (eg, NSCLC with squamous epithelium and / or non-squash epithelial histology)), melanoma (eg, advanced melanoma), digestive / gastrointestinal cancer , Gastric cancer, neurogenic cancer, prostate cancer, bladder cancer, breast cancer; or hematopoietic tumors, such as lymphoma or leukemia.

In some embodiments, Rad-001 has the following structure:

In some embodiments, Rad-001 is ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-. {(1R) -2-[(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23 , 29,35-Hexamethyl-11,36-dioxa-4-aza-tricyclo [30.3.1.04,9] Hexatriaconta-16,24,26,28-tetraene-2,3,10,14 , 20-pentaone).

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an HDM2 ligase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In certain embodiments, HDM2 ligase inhibitors are disclosed in Table 1 (eg, CGM097) or publications cited in Table 1, eg, International Patent Publication WO2011 / 07676 (eg, Formula (I) or Example 106). To. In some embodiments, the HDM2 ligase inhibitor is disclosed, for example, in International Patent Publication WO2011 / 07676 (eg, Formula (I) or Example 106). In some embodiments, the HDM2 ligase inhibitor, eg, CGM097, is as disclosed in publications provided in Table 1 or cited in Table 1, eg, International Patent Publication WO2011 / 07676 (eg, formula (I)). Alternatively, it has a structure (compound or general structure), Example 106). In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, pembrolizumab or one of MSB0010718C) is used in combination with CGM097 to treat the cancers or disorders listed in Table 1, eg solid tumors.

〔式中、
ＺはＣＨ_２またはＮ－Ｒ^４であり；
Ｘはハロゲンであり；
Ｒ^４はＨおよびＣ_１－Ｃ_７－アルキルからなる群から選択され；
Ｒ^６は独立してＨ、Ｒ’Ｏおよび(Ｒ’)_２Ｎからなる群から選択され；
Ｒ^７は独立してＲ’Ｏおよび(Ｒ’)_２Ｎからなる群から選択され；
各Ｒ’は独立してＨ、Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルケニル、ハロ－Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルケニル、Ｃ_３－Ｃ_１２－シクロアルキル、ヘテロシクリル、アリール、ヒドロキシ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルコキシ－Ｃ_１－Ｃ_７アルキル、アミノ－Ｃ_１－Ｃ_７－アルキル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、ヘテロシクリル－Ｃ_１－Ｃ_７－アルキル、アリール－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル、ハロ－Ｃ_１－Ｃ_７－アルキル－カルボニル、ヒドロキシ－Ｃ_１－Ｃ_７－アルキル－カルボニル－、Ｃ_１－Ｃ_７－アルコキシ－Ｃ_１－Ｃ_７－アルキル－カルボニル、アミノ－Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_３－Ｃ_１２－シクロアルキルカルボニル、ヘテロシクリル－Ｃ_１－Ｃ_７－アルキル－カルボニル、アリール－Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル－カルボニル、ヘテロシクリル－カルボニル、アリール－カルボニル、Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル－カルボニル、ヒドロキシ－Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルコキシ－Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｃ_１－Ｃ_７－アルキル、アミノ－Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｃ_１－Ｃ_７－アルキル、ヘテロシクリル－カルボニル－Ｃ_１－Ｃ_７－アルキル、アリール－カルボニル－Ｃ_１－Ｃ_７－アルキル、カルボニル－Ｃ_１－Ｃ_７－アルキル、ヒドロキシル－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルコキシ－カルボニル－Ｃ_１－Ｃ_７－アルキル、アミノ－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｃ_３－Ｃ_１２－シクロアルキル－カルボニル－Ｃ_１－Ｃ_７－アルキル、ヘテロシクリル－カルボニル－Ｃ_１－Ｃ_７－アルキル、アリール－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル－カルボニル－アミノ－Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキルからなる群から選択され、ここで、アリール、ヘテロシクリルおよびＣ_３－Ｃ_１２－シクロアルキルは、非置換であるかまたはＣ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、ハロゲン、ヒドロキシ、Ｃ_１－Ｃ_７－アルコキシ、アミノ、ニトロまたはシアノから選択される１～４置換基により置換されており；
各Ｒ^１は独立してハロゲン、シアノ、ニトロ、Ｃｄ－アルキル、Ｃ_１－Ｃ_７－アルケニル、ハロ－Ｃ_１－Ｃ_７－アルキル、ヒドロキシル、Ｃ_１－Ｃ_７－アルコキシ、アミノ、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ、アミノ－カルボニル－アミノ、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル－アミノ、Ｎ.Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル－アミノ、Ｃ_１－Ｃ_７－アルキル－カルボニル－アミノ、アミノ－カルボニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、Ν,Ν－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、ヒドロキシ－Ｃ_１－Ｃ_７－アルキル、アミノ－Ｃ_１－Ｃ_７－アルキル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキルからなる群から選択され；
ｎは０、１または２であり；
Ｒ^２は
(Ａ)フェニル、２－ピリジルまたは３－ピリジル(該フェニル、２－ピリジルまたは３－ピリジルは、パラ位(イソキノリノンまたはキナゾリノンに対する)を、(Ｒ^３)_２Ｎ－Ｙ－により置換され、ここで、Ｙは存在しない(結合)かまたは(Ｒ_３)_２Ｎ－Ｙ－は

から選択され、該フェニル、２－ピリジルまたは３－ピリジルは、場合によりハロゲン、シアノ、Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、ヒドロキシル、Ｃ_１－Ｃ_７－アルコキシまたはヒドロキシ－Ｃ_１－Ｃ_７－アルキルから選択される１～２のさらなる置換基で置換されていてよい)；
(Ｂ)フェニル、２－ピリジルまたは３－ピリジル(該フェニル、２－ピリジルまたは３－ピリジルは、パラ位(イソキノリノンまたはキナゾリノンに対する)を、シアノ、ハロゲン、ニトロ、Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、ヒドロキシル－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルコキシ－カルボニル、Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_１－Ｃ_７－アルコキシまたは(Ｃ結合)－ヘテロシクリルから選択される置換基で選択され、ここで、(Ｃ結合)－ヘテロシクリルは置換されていないかまたはＣ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、ハロゲン、ヒドロキシ、Ｃ_１－Ｃ_７－アルコキシ、アミノ、ニトロまたはシアノから選択される１～４置換基で置換されており；該フェニル、２－ピリジルおよび３－ピリジルは、場合により、ハロゲン、シアノ、Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、ヒドロキシル、Ｃ_１－Ｃ_７－アルコキシ、(Ｃ結合またはＮ結合)ヘテロシクリル－Ｃ_１－Ｃ_７－アルキルおよびヒドロキシル－Ｃ_１－Ｃ_７－アルキルから独立して選択される１～２のさらなる置換基で置換されていてよい)；または
(Ｃ)オルト位(イソキノリノンまたはキナゾリノンに対する)をＲ^３Ｏで置換され、パラ位またはメタ位を、メチル、クロロ、Ｃ_１－Ｃ_７－アルキル－カルボニルまたはＣ_１－Ｃ_７－アルコキシ－カルボニル－から選択される置換基で置換されているフェニル；
(Ｄ)

(式中、Ｚは、Ｎ、Ｏ、Ｓから選択される１～３ヘテロ原子を含むフェニルとパラ位およびメタ位で環化している４～６員ヘテロ環式環であり、これは、場合によりハロゲン、シアノ、Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、ヒドロキシル、Ｃ_１－Ｃ_７－アルコキシ、ヒドロキシル－Ｃ_１－Ｃ_７－アルキルから選択される１～２のさらなる置換基で置換されていてよい)
から選択される、(Ｃ結合)－ヘテロ環；
(Ｅ)(イソキノリノンまたはキナゾリノンに対する)５位を

で置換されているピラジン－２－イル：
(Ｆ)(イソキノリノンまたはキナゾリノンに対する)６位を

で置換されているピリダジン－３－イル
または
(Ｇ)(イソキノリノンまたはキナゾリノンに対する)５位を

で置換されているピリミジン－２－イル
から選択され、
ここで、各Ｒ^３は、Ｈ、Ｃ_１－Ｃ_７－アルキル、ヒドロキシ－Ｃ_１－Ｃ_７－アルキル、Ｃ_３－Ｃ_１２－シクロアルキル、Ｃ_１－Ｃ_７－アルコキシ－Ｃ_１－Ｃ_７－アルキル－カルボニル、アミノ－Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｎ、Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル－カルボニル、(Ｒ^５)_２Ｎ－Ｃ_３－Ｃ_１２－シクロアルキル、(Ｒ^５)_２Ｎ－Ｃ_１－Ｃ_７－アルキル、(Ｒ^５)_２Ｎ－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、(Ｒ^５)_２Ｎ－Ｃ_３－Ｃ_２－シクロアルキル－カルボニル、Ｒ^５Ｏ－Ｃ_３－Ｃ_１２－シクロアルキル、Ｒ^５Ｏ－Ｃ_１－Ｃ_７－アルキル、Ｒ^５Ｏ－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、Ｒ^５Ｏ－(Ｃ_１－Ｃ_７－アルキル)－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、Ｒ^５Ｏ－(ヒドロキシ－Ｃ_１－Ｃ_７－アルキル)－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、(Ｒ^５)_２Ｎ－ＣＯ－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルコキシカルボニル－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、ヒドロキシカルボニル－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、アミノ－カルボニル－Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、Ｒ^５Ｏ－Ｃ_３－Ｃ_１２－シクロアルキル－カルボニル、(Ｒ^５)_２Ｎ－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｒ^５Ｏ－カルボニル－Ｃ_１－Ｃ_７－アルキル、アリール－Ｃ_１－Ｃ_７－アルキル、ヘテロシクリル－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル、ハロ－Ｃ_１－Ｃ_７－アルキル－カルボニル、ヘテロシクリル－カルボニル、アリール－カルボニル、Ｃ_３－Ｃ_１２－シクロアルキル－カルボニル、Ｃ_３－Ｃ_１２－シクロアルキル－Ｃ_１－Ｃ_７－アルキル、ヘテロシクリル、アリールから独立して選択され、ここで、アリール、ヘテロシクリルおよびＣ_３－Ｃ_１２－シクロアルキルは、非置換であるかまたはハロゲン、Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_３－Ｃ_１２－シクロアルキル－カルボニル、Ｃ_１－Ｃ_７－アルキル－スルホニル、アミノ－スルホニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－スルホニル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－スルホニル、アミノ－カルボニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、オキソ＝から選択される１～４置換基で置換されており、
または２Ｒ^３は、それらが結合しているＮと一体となって、場合によりＮ、ＯまたはＳから選択される１～４のさらなるヘテロ原子を含んでよい３～９員ヘテロ環式環を形成でき、該ヘテロ環式環は置換されていないかまたはハロゲン、ヒドロキシ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル、ハロ－Ｃ_１－Ｃ_７－アルキル、オキソ＝、ヒドロキシル。Ｃ_１－Ｃ_７－アルコキシ、アミノ、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ、ヒドロキシ－カルボニル、Ｃ_１－Ｃ_７－アルコキシ－カルボニル、アミノ－カルボニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_１－Ｃ_７－アルキル－スルホニル、ヘテロシクリル、Ｃ_１－Ｃ_７－アルキル－カルボニル－アミノ、Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノから選択される１～３置換基で置換されており、
各Ｒ^５は、独立して、Ｈ、Ｃ_１－Ｃ_７－アルキル、ヒドロキシ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_１－Ｃ_７－アルキル－カルボニル－Ｃ_１－Ｃ_７－アルキル、アミノ－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルキル－スルホニル、アミノ－スルホニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－スルホニル、Ｎ,Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－スルホニル、ヘテロシクリル－カルボニル、アミノ－カルボニル、Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、Ｎ.Ｎ－ジ－Ｃ_１－Ｃ_７－アルキル－アミノ－カルボニル、Ｃ_３－Ｃ_１２－シクロアルキル－カルボニル、Ｃ_１－Ｃ_７－アルコキシ－カルボニル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルコキシ－カルボニル－Ｎ－Ｃ_１－Ｃ_７－アルキル－アミノ－Ｃ_１－Ｃ_７－アルキル、Ｃ_１－Ｃ_７－アルコキシ－カルボニル、Ｃ_３－Ｃ_１２－シクロアルキル、ヒドロキシ－Ｃ_３－Ｃ_１２－シクロアルキルから選択され、
または２Ｒ^５、それらが結合しているＮと一体となって、場合によりＮ、ＯまたはＳから選択される２、３または４のさらなるヘテロ原子を含んでよい３員、４員、５員、６員、７員、８員または９員ヘテロ環式環を形成してよく、該ヘテロ環式環は置換されていないかまたはＣ_１－Ｃ_７－アルキル、オキソ＝、Ｃ_１－Ｃ_７－アルキル－カルボニル、Ｃ_１－Ｃ_７－アルキル－スルホニル、ヒドロキシ－Ｃ_１－Ｃ_７－アルキルから独立して選択される１～３置換基で置換されており；
ただし、ＺがＣＨ_２、ｎが０または１であり、存在するならば、Ｒ^１がオルト－クロロであり、Ｒ^２がパラ－Ｃ_１－Ｃ_７－アルキル－フェニル、パラ－(ハロ－Ｃ_１－Ｃ_７－アルキル)－フェニル、パラ－Ｃ_１－Ｃ_７－アルコキシ－フェニル、パラ－ハロ－フェニル、パラ－ニトロ－フェニル、パラ－(Ｃ_１－Ｃ_７－アルコキシ－カルボニル)－フェニル、パラ－(ヒドロキシ－カルボニル)－フェニルであり、ここで、フェニルが、場合により１～２のさらなる置換基で置換されていてよく、該置換基が独立してハロおよびメチルから選択されるならば、
Ｒ^６およびＲ^７は両者ともエトキシまたはメトキシではない。〕
の化合物またはその互変異性体またはＮ－オキシドまたは薬学的に許容される塩または溶媒和物である。 In some embodiments, the HDM2 ligase inhibitor is formulated (I).

[In the ceremony,
Z is CH ₂ or N-R ⁴ ;
X is a halogen;
^R4 is selected from the group consisting of H and C1-C7 _- alkyl _;
^R6 is independently selected from the group consisting of H, R'O and ₍ R') 2N;
^R7 is independently selected from the group consisting of R'O and ₍ R') 2N;
Each R'is independently H, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkenyl, halo-C ₁ -C ₇ -alkyl, halo-C ₁ -C ₇ -alkenyl, C ₃ -C ₁₂ -Cycloalkyl, heterocyclyl, aryl, hydroxy-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy-C ₁ -C ₇ alkyl, amino-C ₁ -C ₇ -alkyl, NC ₁ -C ₇ -Alkyl-amino-C ₁ -C ₇ -alkyl, N, N-di-C ₁ -C ₇ -alkyl-amino-C ₁ -C ₇ -alkyl, C ₃ -C ₁₂ -cycloalkyl-C ₁ -C ₇ -alkyl, heterocyclyl-C ₁ -C ₇ -alkyl, aryl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-carbonyl, halo-C ₁ -C ₇ -alkyl-carbonyl, hydroxy-C ₁ -C ₇ -alkyl-carbonyl-, C ₁ -C ₇ -alkoxy-C ₁ -C ₇ -alkyl-carbonyl, amino-C ₁ -C ₇ -alkyl-carbonyl, NC ₁ -C ₇ -alkyl-amino -C ₁ -C ₇ -alkyl-carbonyl, C ₃ -C ₁₂ -cycloalkyl carbonyl, heterocyclyl-C ₁ -C ₇ -alkyl-carbonyl, aryl-C ₁ -C ₇ -alkyl-carbonyl, C ₃ -C ₁₂ -Cycloalkyl-C ₁ -C ₇ -alkyl-carbonyl, heterocyclyl-carbonyl, aryl-carbonyl, C ₁ -C ₇ -alkyl-carbonyl-C ₁ -C ₇ -alkyl, halo-C ₁ -C ₇ -alkyl- Carbonyl, hydroxy-C ₁ -C ₇ -alkyl-carbonyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy-C ₁ -C ₇ -alkyl-carbonyl-C ₁ -C ₇ -alkyl, amino- C ₁ -C ₇ -alkyl-carbonyl-C ₁ -C ₇ -alkyl, heterocyclyl-carbonyl-C ₁ -C ₇ -alkyl, aryl-carbonyl-C ₁ -C ₇ -alkyl, carbonyl-C ₁ -C _7- Alkyl, hydroxyl-carbonyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy-carbonyl-C ₁ -C ₇ -alkyl, amino-carbonyl-C ₁ -C ₇ -alkyl, NC ₁ -C ₇ -alkyl-amino-carbonyl-C ₁ -C ₇ -alkyl, N, N-di-C ₁ -C ₇ -alkyl-amino-carbonyl-C _1- C ₇ -alkyl, C ₃ -C ₁₂ -cycloalkyl-carbonyl-C ₁ -C ₇ -alkyl, heterocyclyl-carbonyl-C ₁ -C ₇ -alkyl, aryl-carbonyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-carbonyl-amino-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-carbonyl-NC ₁ -C ₇ -alkyl-amino-C ₁ -C ₇ -alkyl, halo- C ₁ -C ₇ -alkyl-carbonyl-amino-C ₁ -C ₇ -alkyl, halo-C ₁ -C ₇ -alkyl-carbonyl-N-C ₁ -C ₇ -alkyl-amino-C ₁ -C _7- Selected from the group consisting of alkyl, where aryl, heterocyclyl and C ₃ -C ₁₂ -cycloalkyl are unsubstituted or C1-C ₇ -alkyl, halo-C _{1 -} C ₇ -alkyl, halogen. , Hydroxy, C1 _- C7 _- substituted with 1-4 substituents selected from alkoxy, amino, nitro or cyano;
Each R ¹ is independently halogen, cyano, nitro, Cd-alkyl, C ₁ -C ₇ -alkenyl, halo-C ₁ -C ₇ -alkyl, hydroxyl, C ₁ -C ₇ -alkoxy, amino, NC. ₁ -C ₇ -alkyl-amino, N, N-di-C ₁ -C ₇ -alkyl-amino, amino-carbonyl-amino, NC ₁ -C ₇ -alkyl-amino-carbonyl-amino, N.N. -Di-C ₁ -C ₇ -alkyl-amino-carbonyl-amino, C ₁ -C ₇ -alkyl-carbonyl-amino, amino-carbonyl, NC ₁ -C ₇ -alkyl-amino-carbonyl, Ν, Ν -Di-C ₁ -C ₇ -alkyl-amino-carbonyl, hydroxy-C ₁ -C ₇ -alkyl, amino-C ₁ -C ₇ -alkyl, NC ₁ -C ₇ -alkyl-amino-C _1- C ₇ -alkyl, N, N-di-C ₁ -C ₇ -alkyl-amino-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-carbonyl-amino-C ₁ -C ₇ -alkyl, C Selected from the group consisting of ₁ -C ₇ -alkyl-carbonyl-N-C ₁ -C ₇ -alkyl-amino-C ₁ -C ₇ -alkyl;
n is 0, 1 or 2;
R ² is
(A) Phenyl, 2-pyridyl or 3-pyridyl (where the phenyl, 2-pyridyl or 3-pyridyl is substituted with the para-position (relative to isoquinolinone or quinazolinone) with (R ³ ) _2NY- , where , Y does not exist (bond) or (R ₃ ) ₂ N-Y-

Selected from, the phenyl, 2-pyridyl or 3-pyridyl may optionally be halogen, cyano, C1 _- C7 _- alkyl, halo _- C1 _- C7-alkyl, hydroxyl, C1 _- C7 _- alkoxy or. It may be substituted with 1-2 additional substituents selected from hydroxy-C ₁ -C ₇ -alkyl);
(B) Phenyl, 2-pyridyl or 3-pyridyl (where the phenyl, 2-pyridyl or 3-pyridyl is paraposition (relative to isoquinolinone or quinazolinone), cyano, halogen, nitro, C1 _- C ₇ -alkyl, halo -C ₁ -C ₇ -alkyl, hydroxyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy-carbonyl, C ₁ -C ₇ -alkyl-carbonyl, C ₁ -C ₇ -alkoxy or (C bond) )-Selected with a substituent selected from heterocyclyl, where (C-bonded) -heterocyclyl is unsubstituted or C1 _- C7-alkyl, halo _{-C-1 - C7} -alkyl, halogen, hydroxy , C ₁ -C ₇ -Alkoxy, amino, nitro or cyano substituted with 1-4 substituents; the phenyl, 2-pyridyl and 3-pyridyl may optionally be halogen, cyano, C ₁ -C ₇ -alkyl, halo-C ₁ -C ₇ -alkyl, hydroxyl, C ₁ -C ₇ -alkoxy, (C or N bond) heterocyclyl-C ₁ -C ₇ -alkyl and hydroxyl-C ₁ -C ₇ -Can be substituted with 1-2 additional substituents selected independently of alkyl); or
(C) The ortho position (for isoquinolinone or quinazolinone) is replaced with ^R3O and the para or meta position is methyl, chloro, C1-C7 _- alkyl _- carbonyl or C1 _- C7 _- alkoxy-carbonyl-. Phenyl substituted with a substituent selected from;
(D)

(In the formula, Z is a 4- to 6-membered heterocyclic ring ringed at the para and meta positions with phenyl containing 1-3 heteroatoms selected from N, O and S, which is the case. ₁ to 2 selected from halogen, cyano, C1-C ₇ -alkyl, halo-C ₁ -C ₇ -alkyl, hydroxyl, C ₁ -C ₇ -alkoxy, hydroxyl-C ₁ -C ₇ -alkyl. May be substituted with additional substituents)
Selected from (C bond) -heterocycle;
(E) 5th place (against isoquinolinone or quinazolinone)

Pyrazine-2-yl substituted with:
(F) 6th place (against isoquinolinone or quinazolinone)

Pyridazine-3-yl or
(G) 5th place (against isoquinolinone or quinazolinone)

Selected from pyrimidine-2-yl substituted with,
Here, each R ³ is H, C ₁ -C ₇ -alkyl, hydroxy-C ₁ -C ₇ -alkyl, C ₃ -C ₁₂ -cycloalkyl, C ₁ -C ₇ -alkoxy-C ₁ -C ₇ -Alkyl-carbonyl, amino-C _{1-C 7-alkyl-carbonyl, NC 1-C 7-alkyl-amino-C 1 -C 7 - alkyl - carbonyl} , N, N-di-C ₁ -C ₇ -Alkyl-amino-C ₁ -C ₇ -alkyl-carbonyl, (R ⁵ ) ₂ N-C ₃ -C ₁₂ -cycloalkyl, (R ⁵ ) ₂ N-C ₁ -C ₇ -alkyl, (R ⁵ ) ₂ N-C ₃ -C ₁₂ -Cycloalkyl-C ₁ -C ₇ -alkyl, (R ⁵ ) ₂ N-C ₃ -C ₂ -Cycloalkyl-carbonyl, R ⁵ OC ₃ -C ₁₂ -Cycloalkyl , R ⁵ O-C ₁ -C ₇ -alkyl, R ⁵ O-C ₃ -C ₁₂ -cycloalkyl-C ₁ -C ₇ -alkyl, R ⁵ O- (C ₁ -C ₇ -alkyl) -C ₃ -C ₁₂ -cycloalkyl-C ₁ -C ₇ -alkyl, R ⁵ O- (hydroxy-C ₁ -C ₇ -alkyl) -C ₃ -C ₁₂ -cycloalkyl-C ₁ -C ₇ -alkyl, (R) ⁵ ) ₂ N-CO-C ₃ -C ₁₂ -Cycloalkyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxycarbonyl-C ₃ -C ₁₂ -cycloalkyl-C ₁ -C ₇ -alkyl, Hydroxycarbonyl-C ₃ -C ₁₂ -Cycloalkyl-C ₁ -C ₇ -Alkyl, Amino-Carbonyl-C ₃ -C ₁₂ -Cycloalkyl-C ₁ -C ₇ -Alkyl, R ⁵ O-C ₃ -C ₁₂ -Cycloalkyl-carbonyl, (R ⁵ ) ₂ N-carbonyl-C ₁ -C ₇ -alkyl, R ⁵ O-carbonyl-C ₁ -C ₇ -alkyl, aryl-C ₁ -C ₇ -alkyl, heterocyclyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-carbonyl, halo-C ₁ -C ₇ -alkyl-carbonyl, heterocyclyl-carbonyl, aryl-carbonyl, C ₃ -C ₁₂ -cycloalkyl-carbonyl, C ₃ -C ₁₂ -Cycloalkyl-C Independently selected from ₁ -C ₇ -alkyl, heterocyclyl, aryl, where aryl, heterocyclyl and C ₃ -C ₁₂ -cycloalkyl are unsubstituted or halogen, C1 _- C ₇ -alkyl, Halo-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-carbonyl, C ₃ -C ₁₂ -cycloalkyl-carbonyl, C ₁ -C ₇ -alkyl-sulfonyl, amino-sulfonyl, NC _1- C ₇ -alkyl-amino-sulfonyl, N, N-di-C ₁ -C ₇ -alkyl-amino-sulfonyl, amino-carbonyl, NC ₁ -C ₇ -alkyl-amino-carbonyl, N, N-di It is substituted with 1 to 4 substituents selected from -C ₁ -C ₇ -alkyl-amino-carbonyl, oxo =.
Alternatively, 2R ³ together with the N to which they are bonded form a 3- to 9-membered heterocyclic ring which may optionally contain 1 to 4 additional heteroatoms selected from N, O or S. Yes, the heterocyclic ring is unsubstituted or halogen, hydroxy-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl, halo-C ₁ -C ₇ -alkyl, oxo =, hydroxyl. C ₁ -C ₇ -alkoxy, amino, NC ₁ -C ₇ -alkyl-amino, N, N-di-C ₁ -C ₇ -alkyl-amino, hydroxy-carbonyl, C ₁ -C ₇ -alkoxy- Carbonyl, Amino-carbonyl, NC ₁ -C ₇ -alkyl-amino-carbonyl, N, N-di-C ₁ -C ₇ -alkyl-amino-carbonyl, C ₁ -C ₇ -alkyl-carbonyl, C ₁ 1-3 selected from -C ₇ -alkyl-sulfonyl, heterocyclyl, C ₁ -C ₇ -alkyl-carbonyl-amino, C ₁ -C ₇ -alkyl-carbonyl-N-C ₁ -C ₇ -alkyl-amino Substituted with a substituent and
Each R ⁵ is independently H, C ₁ -C ₇ -alkyl, hydroxy-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-carbonyl, C ₁ -C ₇ -alkyl-carbonyl, C. ₁ -C ₇ -alkyl-carbonyl-C ₁ -C ₇ -alkyl, amino-carbonyl-C ₁ -C ₇ -alkyl, NC ₁ -C ₇ -alkyl-amino-carbonyl-C ₁ -C ₇ -alkyl , N, N-di-C ₁ -C ₇ -alkyl-amino-carbonyl-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkyl-sulfonyl, amino-sulfonyl, NC ₁ -C ₇ -alkyl -Amino-sulfonyl, N, N-di-C ₁ -C ₇ -alkyl-amino-sulfonyl, heterocyclyl-carbonyl, amino-carbonyl, NC ₁ -C ₇ -alkyl-amino-carbonyl, N.N-di -C ₁ -C ₇ -alkyl-amino-carbonyl, C ₃ -C ₁₂ -cycloalkyl-carbonyl, C ₁ -C ₇ -alkoxy-carbonyl-amino-C ₁ -C ₇ -alkyl, C ₁ -C _7- Alkoxy-carbonyl-NC ₁ -C ₇ -alkyl-amino-C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy-carbonyl, C ₃ -C ₁₂ -cycloalkyl, hydroxy-C ₃ -C ₁₂ -Selected from cycloalkyl,
Or 2R5, 3-membered, 4-membered, ⁵ -membered, which may contain an additional 2, 3 or 4 heteroatoms optionally selected from N, O or S together with the N to which they are bonded. A 6-membered, ₇ -membered, 8-membered or 9-membered heterocyclic ring may be formed, the heterocyclic ring being substituted or C1 _- C7 _- alkyl, oxo =, C1 _- C7-. It is substituted with 1-3 substituents independently selected from alkyl-carbonyl, C1 _- C ₇ -alkyl-sulfonyl, hydroxy-C ₁ -C ₇ -alkyl;
However, if Z is CH ₂ , n is 0 or 1, and if present, R ¹ is ortho-chloro and R ² is para-C ₁ -C ₇ -alkyl-phenyl, para- (halo-C). ₁ -C ₇ -alkyl) -phenyl, para-C ₁ -C ₇ -alkoxy-phenyl, para-halo-phenyl, para-nitro-phenyl, para- (C ₁ -C ₇ -alkoxy-carbonyl) -phenyl, Para- (hydroxy-carbonyl) -phenyl, where phenyl may optionally be substituted with one or two additional substituents, if the substituents are independently selected from halo and methyl. ,
Both R ⁶ and R ⁷ are not ethoxy or methoxy. ]
Compound or tautomer thereof or N-oxide or pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the CGM097 has the following structure:

In some embodiments, CGM097 comprises (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-). 1-yl) -trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a PIM kinase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In some embodiments, the PIM kinase inhibitor is a publication cited in Table 1 or Table 1, eg, International Patent Publication WO2010 / 026124 (eg, Formula I or Example 70), European Patent Application EP2344474 and US Patent Publication. It is disclosed in 2010/0056576. In some embodiments, PIM kinase inhibitors are disclosed, for example, in International Patent Publication WO2010 / 026124 (eg, Formula I or Example 70), European Patent Application EP2344744 and US Patent Publication 2010/0056576. In some embodiments, a PIM kinase inhibitor, eg, LGH447, is a publication provided in or cited in Table 1, eg, International Patent Publication WO2010 / 026124 (eg, Formula I or Example 70), European Patent Application. It has a structure (compound or general structure) as disclosed in EP 2344474 and US Patent Publication 2010/0056576. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, penbrolizumab or one of MSB0010718C) is used in combination with a PIM kinase inhibitor to use the cancers or disorders listed in Table 1, eg, hematopoietic tumors. , For example, treating multiple myeloma, myelodysplastic syndrome, myelodysthesia or non-Hodgkin's lymphoma.

〔式中、
Ｘ_ｌ、Ｘ_２、Ｘ_３およびＸ_４は、独立してＣＲ２およびＮから選択され；ただし、Ｘ_１、Ｘ_２、Ｘ_３およびＸ_４の少なくとも１、しかし、２を超えないものがＮであり；
Ｙは、シクロアルキル、部分的不飽和シクロアルキルおよびヘテロシクロアルキルからなる群から選択され、ここで、該群の各メンバーは、最大４置換基で置換されていてよく；
Ｚ_２およびＺ_３は、独立してＣＲ_１２およびＮから選択され；ただし、Ｚ_２およびＺ_３の１を超えて、Ｎであってはならず；
Ｒ_１は、水素、－ＮＨＲ_３、ハロ、ヒドロキシル、アルキル、シアノおよびニトロからなる群から選択され；
Ｒ_２およびＲ_１２は、各々独立して、水素、ハロ、ヒドロキシル、ニトロ、シアノ、ＳＯ_３Ｈおよび置換または非置換アルキル、アルケニル、アルキニル、アルコキシ、アミノ、シクロアルキル、ヘテロシクロアルキルおよび部分的飽和シクロアルキルからなる群から選択され；
Ｒ_３は、水素、－ＣＯ－Ｒ_４および置換または非置換アルキル、シクロアルキル、ヘテロシクリル、アリールおよびヘテロアリールからなる群から選択され；
Ｒ_４は、アルキル、置換アルキル、アルコキシ、置換アルコキシ、アミノ、置換アミノおよびアルキルアミノからなる群から選択され；
Ｒ_５は、置換または非置換アリール、Ｃ_３－Ｃ_７シクロアルキル、ヘテロアリール、部分的不飽和シクロアルキルおよびアルキルから選択される基であり、ここで、該置換Ｒ_５基の各々は、ハロ、シアノ、アミノ、Ｃ_１－４アルキル、Ｃ_３－６シクロアルキル、アルコキシ、ニトロ、カルボキシ、カルボニル、カルボアルコキシ、アミノカルボキシ、置換アミノカルボニル、アミノスルホニル、置換アミノスルホニルおよびアルコキシアルキルから選択される４個までの置換基で置換されていてよい。〕
の化合物またはその薬学的に許容される塩である。 In some embodiments, the PIM kinase inhibitor is formulated (I).

[In the ceremony,
X _l , X ₂ , X ₃ and X ₄ are independently selected from CR 2 and N; however, at least one of X ₁ , X ₂ , X ₃ and X ₄ but not more than 2 is N. can be;
Y is selected from the group consisting of cycloalkyl, partially unsaturated cycloalkyl and heterocycloalkyl, where each member of the group may be substituted with up to 4 substituents;
Z ₂ and Z ₃ are independently selected from CR ₁₂ and N; however, they must not be N beyond 1 of Z ₂ and Z ₃ ;
R ₁ is selected from the group consisting of hydrogen, -NHR ₃ , halo, hydroxyl, alkyl, cyano and nitro;
R ₂ and R ₁₂ are independently hydrogen, halo, hydroxyl, nitro, cyano, SO _3H and substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino, cycloalkyl, heterocycloalkyl and partially saturated, respectively. Selected from the group consisting of cycloalkyl;
R ₃ is selected from the group consisting of hydrogen, -CO-R ₄ and substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
_R4 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino and alkylamino;
R ₅ is a group selected from substituted or unsubstituted aryl, C3 _- C7 cycloalkyl, heteroaryl, partially unsaturated cycloalkyl and alkyl, _{where each of the substituted R 5 groups} is a halo. , Cyano, amino, C _1-4 alkyl, C _3-6 cycloalkyl, alkoxy, nitro, carboxy, carbonyl, carboalkoxy, aminocarboxy, substituted aminocarbonyl, aminosulfonyl, substituted aminosulfonyl and alkoxyalkyl 4 It may be substituted with up to a substituent. ]
Compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the LGH447 has the following structure:

In some embodiments, LGH447 comprises N-(4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -3-. Fluoropicoline amide.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a HER3 kinase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In some embodiments, HER3 kinase inhibitors are disclosed in Table 1 (eg, LJM716) or the publications cited in Table 1. In some embodiments, HER3 kinase inhibitors are disclosed, for example, in International Patent Publication No. 2012/022814 and US Pat. No. 8,735,551. In some embodiments, LJM716 is a monoclonal antibody as disclosed in the publications provided in Table 1 or cited in Table 1. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, pembrolizumab or one of MSB0010718C) is used in combination with LJM716 for the cancers or disorders listed in Table 1, such as solid tumors, such as gastric cancer. Treat esophageal cancer, breast cancer, head and neck cancer, gastric cancer or gastrointestinal / gastrointestinal cancer treatment.

In some embodiments, a HER3 kinase inhibitor, eg, LJM716, is an anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551. Is. In other embodiments, the HER3 kinase inhibitor, eg, LJM716, is a heavy chain variable region CDR1 of SEQ ID NO: 128; CDR2 of SEQ ID NO: 129; CDR3 of SEQ ID NO: 130; and An anti-HER3 monoclonal comprising the light chain variable region CDR1 of SEQ ID NO: 131; CDR2 of SEQ ID NO: 132; and CDR3 of SEQ ID NO: 133, eg, underlined in the heavy and light chain variable region sequences of LJM716 below. An antibody or an antigen-binding fragment thereof. In some embodiments, the HER3 kinase inhibitor, eg, LJM716, is a conformational epitope of the HER3 receptor, eg, an amino acid residue 265 within domain 2 of the HER3 receptor of SEQ ID NO: 1, US 8,735,551. An anti-HER3 monoclonal antibody or antigen-binding fragment thereof that recognizes the conformational epitopes of amino acids 571, 582-584, 596-597, 600-602 and 609-615 within ~ 277 and 315 and domain 4.

The amino acid sequences of the heavy and light chain variable regions of LJM716 include at least:
Heavy chain variable region (SEQ ID NO: 141 as disclosed in US 8,735,551) (SEQ ID NO: 8)
EVQLLESGGGLVQPGGSLRLSCAASGFTFS SYAMS WVRQAPGKGLEWVS AINSQGKSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR WGDEGFDI WGQGTLVTVSS
Light chain variable region (SEQ ID NO: 140 as disclosed in US 8,735,551) (SEQ ID NO: 9)
DIQMTQSPSSLSASVGDRVTITC RASQGISNWLA WYQQKPGKAPKLLIY GASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQYSSFPTT FGQGTKVEIK

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an HDAC inhibitor to use a cancer, eg, a cancer described herein (eg, Table 1). Disclosed in the treatment of cancer). In some embodiments, the HDAC inhibitor is a publication cited in Table 1 (eg, LBH589) or Table 1, eg, International Patent Publication Nos. 2014/072493 and 2002/022577 (eg, Formula (I) and Example 200). ) And European patent application EP1870399. In some embodiments, HDAC inhibitors are disclosed, for example, in International Patent Publication 2014/072493 and 2002/022577 (eg, Formula (I) and Example 200) and European Patent Application EP1870399. In some embodiments, LBH589 provides publications provided in or cited in Table 1, such as International Patent Publication Nos. 2014/072493 and 2002/0225277 (eg, Formula (I) and Example 200) and European Patents. It has a structure (compound or general) as disclosed in application EP1870399. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nibolumab, penbrolizumab or one of MSB0010718C) is used in combination with LBH589 to use the cancers or disorders listed in Table 1, eg, solid tumors, eg, bone. Cancer, small cell lung cancer, respiratory / chest cancer, prostate cancer, non-small cell lung cancer (NSCLC), neurogenic cancer, gastric cancer, melanoma, breast cancer, pancreatic cancer, colorectal cancer, kidney cancer or head and neck cancer or liver Cancer; or treat hematopoietic tumors, such as multiple myeloma, hematopoietic disorders, myelodystrophy syndrome, lymphoma (eg, non-hodgkin lymphoma) or leukemia (eg, myeloid leukemia).

〔式中、
Ｒ_１はＨ、ハロまたは直鎖Ｃ_１－Ｃ_６アルキル(特にメチル、エチルまたはｎ－プロピルであり、該メチル、エチルおよびｎ－プロピル置換基は、非置換であるかまたは下にアルキル置換基について記載する１以上の置換基で置換されている)；
Ｒ_２は、Ｈ、Ｃ_１－Ｃ_１０アルキル、(例えばメチル、エチルまたは－ＣＨ_２ＣＨ_２－ＯＨ)、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキルアルキル、シクロアルキルアルキル(例えば、シクロプロピルメチル)、アリール、ヘテロアリール、アリールアルキル(例えばベンジル)、ヘテロアリールアルキル(例えばピリジルメチル)、－(ＣＨ_２)_ｎＣ(Ｏ)Ｒ_６、－(ＣＨ_２)_ｎＯＣ(Ｏ)Ｒ_６、アミノアシル、ＨＯＮ－Ｃ(Ｏ)－ＣＨ＝Ｃ(Ｒ_１)－アリール－アルキル－および－(ＣＨ_２)_ｎＲ_７から選択され；
Ｒ_３およびＲ_４は、同一または異なり、独立してＨ、Ｃ_１－Ｃ_６アルキル、アシルまたはアシルアミノであるかまたはＲ_３およびＲ_４は、それらが結合している炭素と一体となって、Ｃ＝Ｏ、Ｃ＝ＳまたはＣ＝ＮＲ_８であるかまたはＲ_２はそれが結合している窒素と一体となっておよびＲ_３はそれが結合している炭素と一体となってＣ_４－Ｃ_９ヘテロシクロアルキル、ヘテロアリール、ポリヘテロアリール、非芳香族ポリヘテロ環または混合型アリールおよび非アリールポリヘテロ環を形成でき；
Ｒ_５は、Ｈ、Ｃ_１－Ｃ_６アルキル、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、アシル、アリール、ヘテロアリール、アリールアルキル(例えば、ベンジル)、ヘテロアリールアルキル(例えば、ピリジルメチル)、芳香族多環、非芳香族多環、混合型アリールおよび非アリール多環、ポリヘテロアリール、非芳香族ポリヘテロ環および混合型アリールおよび非アリールポリヘテロ環から選択され；
ｎ、ｎ_１、ｎ_２およびｎ_３は、同一または異なり、独立して０～６から選択され、ｎ１が１～６であるとき、各炭素原子は、場合によりかつ独立してＲ_３および／またはＲ_４で置換されていてよく；
ＸおよびＹは、同一または異なり、独立してＨ、ハロ、Ｃ_１－Ｃ_４アルキル、例えばＣＨ_３およびＣＦ_３、ＮＯ_２、Ｃ(Ｏ)Ｒ_１、または_９、ＳＲ_９、ＣＮおよびＮＲ_１０Ｒ_１１から選択され；
Ｒ_６は、Ｈ、Ｃ_１－Ｃ_６アルキル、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、シクロアルキルアルキル(例えば、シクロプロピルメチル)、アリール、ヘテロアリール、アリールアルキル(例えば、ベンジル、２－フェニルエテニル)、ヘテロアリールアルキル(例えば、ピリジルメチル)、または_１２およびＮＲ_１３Ｒ_１４から選択され；
Ｒ_７は、ＯＲ_１５、ＳＲι_５、Ｓ(Ｏ)Ｒ_１６、ＳＯ_２Ｒ_１７、ＮＲ_１３Ｒι_４およびＮＲ_１２ＳＯ_２Ｒ_６から選択され；
Ｒ_８は、Ｈ、または_１５、ＮＲ_１３Ｒ_１４、Ｃ_１－Ｃ_６アルキル、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル(例えば、ベンジル)およびヘテロアリールアルキル(例えば、ピリジルメチル)から選択され；
Ｒ_９は、Ｃ_１－Ｃ_６アルキル、例えば、ＣＨ_３およびＣＦ_３、Ｃ(Ｏ)－アルキル、例えばＣ(Ｏ)ＣＨ_３およびＣ(Ｏ)ＣＦ_３から選択され；
Ｒ_１０およびＲ_１１は、同一または異なり、独立してＨ、Ｃ_１－Ｃ_４アルキルおよび－Ｃ(Ｏ)－アルキルから選択され；
Ｒ_１２は、Ｈ、Ｃ_１－Ｃ_６アルキル、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキルアルキル、アリール、混合型アリールおよび非アリール多環、ヘテロアリール、アリールアルキル(例えば、ベンジル)およびヘテロアリールアルキル(例えば、ピリジルメチル)から選択され；
Ｒ_１３およびＲ_１４は、同一または異なり、独立してＨ、Ｃ_１－Ｃ_６アルキル、
Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル(例えば、ベンジル)、ヘテロアリールアルキル(例えば、ピリジルメチル)、アミノアシルから選択されるかまたはＲ_１３およびＲ_１４は、それらが結合している窒素と一体となって、Ｃ_４－Ｃ_９ヘテロシクロアルキル、ヘテロアリール、ポリヘテロアリール、非芳香族ポリヘテロ環または混合型アリールおよび非アリールポリヘテロ環であり；
Ｒ_１５は、Ｈ、Ｃｉ－Ｃｅアルキル、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキルおよび(ＣＨ_２)_ｍＺＲ₁₂から選択され；
Ｒ_１６は、Ｃ_１－Ｃ_６アルキル、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、アリール、ヘテロアリール、ポリヘテロアリール、アリールアルキル、ヘテロアリールアルキルおよび(ＣＨ_２)_ｍＺＲ₁₂から選択され；
Ｒ_１７は、Ｃ_１－Ｃ_６アルキル、Ｃ_４－Ｃ_９シクロアルキル、Ｃ_４－Ｃ_９ヘテロシクロアルキル、アリール、芳香族多環、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ポリヘテロアリールから選択され、
ｍは０～６から選択される整数であり；
Ｚは、Ｏ、ＮＲ_１３、ＳおよびＳ(Ｏ)から選択される。〕
の化合物またはその薬学的に許容される塩である。 In some embodiments, the HDAC inhibitor is formulated (I).

[In the ceremony,
R ₁ is H, halo or linear C ₁ -C ₆ alkyl (particularly methyl, ethyl or n-propyl, the methyl, ethyl and n-propyl substituents being unsubstituted or under alkyl substituents. Substituted with one or more substituents described in);
R ₂ is H, C ₁ -C ₁₀ alkyl, (eg, methyl, ethyl or -CH ₂ CH ₂ -OH), C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, C ₄ -C ₉ Heterocycloalkylalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (eg pyridylmethyl),-(CH ₂ ) _n C (O) R ₆ , -(CH ₂ ) _n OC (O) R ₆ , aminoacyl, HON-C (O) -CH = C (R ₁ ) -aryl-alkyl- and-(CH ₂ ) _n R ₇ ;
R ₃ and R ₄ are the same or different and independently H, C ₁ -C ₆ alkyl, acyl or acyl amino, or R ₃ and R ₄ are integrated with the carbon to which they are attached. C = O, C = S or C = NR ₈ or R ₂ is integrated with the nitrogen to which it is attached and R ₃ is integrated with the carbon to which it is attached C _{4- C9} Heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle can be formed;
R5 is H, C _{1 -} C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (eg, benzyl), heteroarylalkyl (eg, benzyl). , Pyridylmethyl), aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryls, non-aromatic polyheterocycles and mixed aryl and non-aryl polyheterocycles;
n, n ₁ , n ₂ and n ₃ are the same or different and are independently selected from 0-6, and when n1 is 1-6, each carbon atom is optionally and independently R ₃ and / Or it may be replaced with _R4 ;
X and Y are the same or different and independently H, halo, C1- _C4 alkyl, eg CH ₃ and CF _3, NO ₂ , C (O) R ₁ , or ₉ , SR ₉ , CN and _{NR 10 .} Selected from R ₁₁ ;
R ₆ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl (eg). , Benzyl, 2-phenylethenyl), heteroarylalkyl (eg pyridylmethyl), or ₁₂ and NR _{13 R14} ;
R ₇ is selected from OR ₁₅ , SR ι ₅ , S (O) R ₁₆ , SO ₂ R ₁₇ , NR ₁₃ R ι ₄ and NR ₁₂ SO ₂ R ₆ ;
R ₈ is H, or ₁₅ , NR ₁₃ R ₁₄ , C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg, benzyl). And heteroarylalkyl (eg, pyridylmethyl);
R ₉ is selected from C1 _- C ₆ alkyls such as CH ₃ and CF ₃ , C (O) -alkyls such as C (O) CH ₃ and C (O) CF ₃ ;
R ₁₀ and R ₁₁ are the same or different and are independently selected from H, C ₁ -C ₄ alkyl and -C (O) -alkyl;
R ₁₂ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkyl alkyl, aryl, mixed aryl and non-aryl polycycles. , Heteroaryl, arylalkyl (eg, benzyl) and heteroarylalkyl (eg, pyridylmethyl);
R ₁₃ and R ₁₄ are the same or different and independently H, C1 _{-C 6 alkyl} ,
Selected from C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg, benzyl), heteroarylalkyl ₍ eg, pyridylmethyl), aminoacyl or R13 and R14, together with the nitrogen to which they are attached, is a _C4 - _C9 heterocycloalkyl, heteroaryl, _{polyheteroaryl} , non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle. ;
R ₁₅ is selected from H, Ci-Ce alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ . ;
R ₁₆ includes C1 _- C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR. Selected from ₁₂ ;
R ₁₇ is selected from C1 _- C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl. Being done
m is an integer selected from 0 to 6;
Z is selected from O, NR ₁₃ , S and S (O). ]
Compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the LBH589 has the following structure:

In some embodiments, LBH589 is (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a Janus kinase inhibitor to use a cancer, eg, a cancer described herein (eg, table). The cancer disclosed in 1) is treated. In some embodiments, the Janus kinase inhibitor is a publications cited in Table 1 (eg, INC424) or Table 1, eg, International Patent Publication No. WO2007 / 070514 (eg, Formula (I) or Example 67) and WO2014 /. It is disclosed in 018632, European Patent Application EP2474545 and US Pat. No. 7,598,257. In some embodiments, Janus kinase inhibitors are described, for example, in International Patent Publication No. 2007/070514 (eg, Formula (I) or Example 67) and 2014/018632, European Patent Application EP2474545 and US Pat. No. 7,598,257. Disclosure in issue. In some embodiments, the Janus kinase inhibitor, eg, INC424, is a publication provided in or cited in Table 1, eg, International Patent Publication No. WO2007 / 070514 (eg, Formula (I) or Example 67) and It has a structure (compound or general) as disclosed in WO2014 / 018632, European Patent Application EP2474545 and US Pat. No. 7,598,257. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, nivolumab, penbrolizumab or one of MSB0010718C) is used in combination with INC424 for a cancer or disorder listed in Table 1, eg, a solid tumor, eg, a leukemia. Treat cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer; or hematopoietic tumors, such as multiple myeloma, lymphoma (eg, non-Hodikin lymphoma) or leukemia (eg, myeloid leukemia, lymphocytic leukemia). In some embodiments, the cancer is identified as having or having a JAK mutation. In some embodiments, the JAK mutation is a JAK2 V617F mutation.

〔式中、
Ａ^１およびＡ^２は、独立してＣおよびＮから選択され；
Ｔ、ＵおよびＶは、独立してＯ、Ｓ、Ｎ、ＣＲ^５およびＮＲ^６から選択され；ここで、Ａ^１、Ａ^２、Ｕ、ＴおよびＶにより形成される５員環は芳香族であり；
ＸはＮまたはＣＲ^４であり；
ＹはＣ_１－８アルキレン、Ｃ_２－８アルケニレン、Ｃ_２－８アルキニレン、(ＣＲ^１１Ｒ^１２)ｐ－(Ｃ_３－１０シクロアルキレン)－(ＣＲ^１１Ｒ^Ｉ２)_ｑ、(ＣＲ^ｌＩＲ^１２)_ｐ－(アリーレン)－(ＣＲ^１１Ｒ^１２)_ｑ、(ＣＲ^１１Ｒ^１２)_ｐ－(Ｃ_１－１０ヘテロシクロアルキレン)－(ＣＲ^１１Ｒ^１２)_ｑ、(ＣＲ^１１Ｒ^１２)ｐ－(ヘテロアリーレン)－(ＣＲ^１１’Ｒ^１２)_ｑ、(ＣＲ^１１Ｒ^１２)ｐＯ(ＣＲ^１１Ｒ^１２)、(ＣＲ^１１Ｒ^１２)_ｐＳ(ＣＲ^１１Ｒ^１２)、(ＣＲ^１１Ｒ^１２)_ｐＣ(Ｏ)(ＣＲ^１１Ｒ^１２)_ｑ、(ＣＲ^１(ＣＲ^１ＩＲ^１２)_ｐＣ(Ｏ)ＮＲ^ｃ(ＣＲ^Ｉ１Ｒ^１２)_ｑ、(ＣＲ^１１Ｒ^Ｉ２)_ｐＣ(Ｏ)Ｏ(ＣＲ^１１Ｒ^Ｉ２)_ｑ、(ＣＲ^１１Ｒ^１２)_ｐＯＣ(Ｏ)(ＣＲ^１１Ｒ^１２)_ｑ、(ＣＲ^１１Ｒ^Ｉ２)_ｐＮＲ^ｃ(ＣＲ^１１Ｒ^Ｉ２)_ｑ、(ＣＲ^１１Ｒ^１２)_ｐＮＲ^ｃＣ(Ｏ)ＮＲ^ｄ(ＣＲ^１１Ｒ^１２)_ｑ、(ＣＲ^１１Ｒ^１２)ｐＳ(Ｏ)(ＣＲ^１１Ｒ^１２)_ｑ、(ＣＲ”Ｒ^１２)_ｐＳ(Ｏ)ＮＲ^ｃ(ＣＲ^１１Ｒ^１２)_ｑ、(ＣＲ^１１Ｒ^１２)ｐＳ(Ｏ)_２(ＣＲ^１１Ｒ^１２)_ｑまたは(ＣＲ^１１Ｒ^１２)ｐＳ(Ｏ)_２ＮＲ^ｃ(ＣＲ^１１Ｒ^１２)_ｑであり、ここで、該Ｃ_１－８アルキレン、Ｃ_２._８アルケニレン、Ｃ_２－_８アルキニレン、シクロアルキレン、アリーレン、ヘテロシクロアルキレンまたはヘテロアリーレンは、場合により－Ｄ’－Ｄ^２－Ｄ^３－Ｄ^４から独立して選択される１、２または３置換基で置換されていてよく；
ＺはＨ、ハロ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃｉ_－４ハロアルキル、ハロスルファニル、Ｃ_１－４ヒドロキシアルキル、Ｃ_１－４シアノアルキル、＝Ｃ－Ｒ^！、＝Ｎ－Ｒ^！、Ｃｙ^１、ＣＮ、ＮＯ_２、ＯＲ、ＳＲ^ａ、Ｃ(Ｏ)Ｒ^ｂ、Ｃ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｃ(Ｏ)ＯＲ^３、ＯＣ(Ｏ)Ｒ^６、ＯＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(Ｏ)Ｒ^ｂ、ＮＲ^ｃＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^０Ｃ(Ｏ)ＯＲ^３、Ｃ(＝ＮＲ’)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(＝ＮＲ^ｉ)ＮＲ^ｃＲ^ｄ、Ｓ(Ｏ)Ｒ^ｂ、Ｓ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｓ(Ｏ)_２Ｒ^ｂ、ＮＲ^ｃＳ(Ｏ)_２Ｒ^ｂ、Ｃ(＝ＮＯＨ)Ｒ^ｂ、：５アルキル)Ｒ^ｂおよびＳ(Ｏ)_２ＮＲ^ｃＲ^ｄであり、ここで、該Ｃ_１－８アルキル、Ｃ_２－８アルケニルまたはＣ_２－８アルキニルは、場合によりハロ、Ｃ_ｗアルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃｉ_－４ハロアルキル、ハロスルファニル、Ｃ_１－４ヒドロキシアルキル、Ｃｉ_－４シアノアルキル、Ｃｙ^１、ＣＮ、ＮＯ_２、ＯＲ”、ＳＲ”、Ｃ(Ｏ)Ｒ^ｂ、Ｃ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｃ(Ｏ)ＯＲ”、ＯＣ(Ｏ)Ｒ^ｂ、ＯＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(Ｏ)Ｒ^ｂ、ＮＲ℃(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(Ｏ)ＯＲ^ａ、Ｃ(＝ＮＲ^ｉ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(＝ＮＲ’)ＮＲ°Ｒ^ｄ、Ｓ(Ｏ)Ｒ^ｂ、Ｓ(Ｏ)ＮＲ°Ｒ^ｄ、Ｓ(Ｏ)_２Ｒ^ｂ、ＯＮＲ^ｃＳ(Ｏ)_２Ｒ^ｂ、Ｃ(＝ＮＯＨ)Ｒ^ｂ、Ｃ(＝ＮＯ(Ｃ_１－６アルキル))Ｒ^ｂおよびＳ(Ｏ)_２ＮＲ^ｃＲ^ｄから独立して選択される１、２、３、４、５または６置換基で置換されていてよく；ここで、ＺはＨであり、ｎは１であり；
または－(Ｙ)_ｎ－Ｚ部分は、ｉ)該部分が結合しているＡ^２、ii)ＴまたはＶのＲ^５またはＲ^６およびiii)ＴまたはＶのＲ^５またはＲ^６が結合しているＣまたはＮ原子と一体となって、Ａ^１、Ａ^２、Ｕ、ＴおよびＶにより形成された５員環と縮合した４～２０員アリール、シクロアルキル、ヘテロアリールまたはヘテロシクロアルキル環を形成し、ここで、該４～２０員アリール、シクロアルキル、ヘテロアリールまたはヘテロシクロアルキル環は、場合により－(Ｗ)_ｍ－Ｑから独立して選択される１、２、３、４または５置換基で置換されていてよく；
ＷはＣ_１－８アルキレニル、Ｃ_２－８アルケニレニル、Ｃ_２－８アルキニレニル、Ｏ、Ｓ_、Ｃ(Ｏ)、Ｃ(Ｏ)ＮＲ^ｃ’、Ｃ(Ｏ)Ｏ、ＯＣ(Ｏ)、ＯＣ(Ｏ)ＮＲ^ｃ’、ＮＲ^ｃ’、ＮＲ^ｃ’Ｃ(Ｏ)ＮＲ^ｄ’、Ｓ(Ｏ)、Ｓ(Ｏ)ＮＲ^ｃ’、Ｓ(Ｏ)_２またはＳ(Ｏ)_２ＮＲ^ｃ”であり；
ＱはＨ、ハロ、ＣＮ、ＮＯ_２、Ｃｉ_－８アルキル、Ｃ_２－Ｓアルケニル、Ｃ_２－８アルキニル、ｄ._８ハロアルキル、ハロスルファニル、アリール、シクロアルキル、ヘテロアリールまたはヘテロシクロアルキルであり、ここで、該Ｃ_１－８アルキル、Ｃ_２－８アルケニル、Ｃ_２－８アルキニル、Ｃｉ_－８ハロアルキル、アリール、シクロアルキル、ヘテロアリールまたはヘテロシクロアルキルは、場合によりハロ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃ_１－４ハロアルキル、ハロスルファニル、Ｃ_１－４ヒドロキシアルキル、Ｃ_１－４シアノアルキル、Ｃｙ^２、ＣＮ、ＮＯ_２、ＯＲ^３’、ＳＲ^ａ’、Ｃ(Ｏ)Ｒ^ｂ”、Ｃ(Ｏ)ＮＲ^ｃ’Ｒ^ｄ’、Ｃ(Ｏ)ＯＲ^３’、ＯＣ(Ｏ)Ｒ”^’、ＯＣ(Ｏ)ＮＲ^０Ｒ”^’、ＮＲ°Ｒ^ｄ’、ＮＲ°^’Ｃ(Ｏ)Ｒ^ｂ’、ＮＲ^ｃ”Ｃ(Ｏ)ＮＲ°^’Ｒ^ｄ”、ＮＲ°^’Ｃ(Ｏ)ＯＲ^ａ’、Ｓ(Ｏ)Ｒ^ｂ”、Ｓ(Ｏ)ＮＲ^ｃ’Ｒ^ｄ”、Ｓ(Ｏ)_２Ｒ^ｂ＞、ＮＲ°^’Ｓ(Ｏ)_２Ｒ^ｂおよびＳ(Ｏ)_２ＮＲ°^’Ｒ^ｄ’から独立して選択される１、２、３または４置換基で置換されていてよく；
Ｃｙ^１およびＣｙ^２は、独立してアリール、ヘテロアリール、シクロアルキルおよびヘテロシクロアルキルから選択され、各々、場合によりハロ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃ_１－４ハロアルキル、ハロスルファニル、Ｃ_１－４ヒドロキシアルキル、Ｃ_１－４シアノアルキル、ＣＮ、ＮＯ_２、０Ｒ^ａ”、ＳＲ^ａ”、Ｃ(Ｏ)Ｒ^ｂ”、Ｃ(Ｏ)ＮＲ^ｃ”Ｒ^ｄ”、Ｃ(Ｏ)ＯＲ^３”、ＯＣ(Ｏ)Ｒ^ｂ”、ＯＣ(Ｏ)ＮＲ°^”Ｒ^ｄ”、ＮＲ^ｃ”Ｒ^ｄ”、ＮＲ^ｃ”Ｃ(Ｏ)Ｒ^ｂ”、ＮＲ^ｃ”Ｃ(Ｏ)ＯＲ^ａ”、ＮＲ°^”Ｓ(Ｏ)Ｒ^ｂ”、ＮＲ°^”Ｓ(Ｏ)_２Ｒ^ｂ”、Ｓ(Ｏ)Ｒ^ｂ”、Ｓ(Ｏ)ＮＲ^ｃ”Ｒ^ｄ”、Ｓ(Ｏ)_２Ｒ^ｂ”およびＳ(Ｏ)_２ＮＲ°^”Ｒ^ｄ”から独立して選択される１、２、３、４または５置換基で置換されていてよく；
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、独立してＨ、ハロ、Ｃ_１－６アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＣＮ、ＮＯ_２、または^７、ＳＲ^７、Ｃ(Ｏ)Ｒ^８、Ｃ(Ｏ)ＮＲ^９Ｒ^１０、Ｃ(Ｏ)ＯＲ^７ＯＣ(Ｏ)Ｒ^８、ＯＣ(Ｏ)ＮＲ^９Ｒ^１０、ＮＲ^９Ｒ^１０、ＮＲ^９Ｃ(Ｏ)Ｒ^８、ＮＲ^０Ｃ(Ｏ)ＯＲ^７、Ｓ(Ｏ)Ｒ^８、Ｓ(Ｏ)ＮＲ^９Ｒ^１０、Ｓ(Ｏ)_２Ｒ^８、ＮＲ^９Ｓ(Ｏ)_２Ｒ^８およびＳ(Ｏ)_２ＮＲ^９Ｒ^１０から選択され；
Ｒ^５はＨ、ハロ、Ｃ_)－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃ_Ｎ４ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、または^７、ＳＲ^７、Ｃ(Ｏ)Ｒ^８、Ｃ(Ｏ)ＮＲ^９Ｒ^１０、Ｃ(Ｏ)ＯＲ^７、ＯＣ(Ｏ)Ｒ^８、ＯＣ(Ｏ)ＮＲ^９Ｒ^１０、ＮＲ^９Ｒ^１０、ＮＲ^９Ｃ(Ｏ)Ｒ^８、ＮＲ^９Ｃ(Ｏ)ＯＲ^７、Ｓ(Ｏ)Ｒ^８、Ｓ(Ｏ)ＮＲ^９Ｒ^１０、Ｓ(Ｏ)_２Ｒ^８、ＮＲ^９Ｓ(Ｏ)_２Ｒ^８またはＳ(Ｏ)_２ＮＲ^９Ｒ^１０でありであり；
Ｒ^６はＨ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃ_１－４ハロアルキル、または^７、Ｃ(Ｏ)Ｒ^８、Ｃ(Ｏ)ＮＲ^９Ｒ^１０、Ｃ(Ｏ)ＯＲ^７、Ｓ(Ｏ)Ｒ^８、Ｓ(Ｏ)ＮＲ^９Ｒ^１０、Ｓ(Ｏ)_２Ｒ^８またはＳ(Ｏ)_２ＮＲ^９Ｒ^１０であり；
Ｒ^７はＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルであり；
Ｒ^８はＨ、Ｃ_１－６アルキル、Ｃｉ_－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２._６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルであり；
Ｒ^９およびＲ^１０は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２._６アルキニル、Ｃ_１－６アルキルカルボニル、アリールカルボニル、Ｃ_１－６アルキルスルホニル、アリールスルホニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され；
またはＲ^９およびＲ^１０は、それらが結合しているＮ原子と一体となって、４員、５員、６員または７員ヘテロシクロアルキル基を形成し；
Ｒ^１１およびＲ^１２は、独立してＨおよび－Ε^ι－Ε^２－Ε^３－Ε^４から選択され；
Ｄ^１およびＥ^１は、独立して存在しないか、または独立してＣ_１－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２._６アルキニレン、アリーレン、シクロアルキレン、ヘテロアリーレンおよびヘテロシクロアルキレンから選択され、ここで、Ｃｉ_－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２._６アルキニレン、アリーレン、シクロアルキレン、ヘテロアリーレンおよびヘテロシクロアルキレンの各々は、場合によりハロ、ＣＮ、ＮＯ_２、Ｎ_３、ＳＣＮ、ＯＨ、Ｃｉ._６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２._８アルコキシアルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルコキシ、アミノ、Ｃ_１－６アルキルアミノおよびＣ_２－８ジアルキルアミノから独立して選択される１、２または３置換基で置換されていてよく；
Ｄ^２およびＥ^２は、独立して存在しないか、または独立してＣ_１－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２－６アルキニレン、(Ｃ_１－６アルキレン)_ｒ－Ｏ－(Ｃ_１－６アルキレン)_ｓ、(Ｃ_１－６アルキレン)_ｒ－Ｓ－(Ｃ_１－６アルキレン)_ｓ、(Ｃ_１－６アルキレン)_ｒ－ＮＲ^ｅ－(Ｃ_１－６アルキレン)_ｓ、(Ｃ,._６アルキレン)_ｒ－ＣＯ－(Ｃ_１－６アルキレン)_ｓ、(Ｃ_１－６アルキレン)_ｒ－ＣＯＯ－(Ｃ_１－６アルキレン)_ｓ、(Ｃ_１－６アルキレン)_ｒ－ＣＯＮＲ^ｅ－(Ｃ_１－６アルキレン)_ｓ、(Ｃ_１－６アルキレン)_ｒ－ＳＯ－(Ｃ_１－６アルキレン)_ｓ、(Ｃ_１－６アルキレン)_ｒ－ＳＯ_２－(Ｃ_１－６アルキレン)_ｓ、(Ｃ_１－６アルキレン)_ｒ－ＳＯＮＲ^ｃ－(Ｃ_１－６アルキレン)_ｓおよび(Ｃ_１－６アルキレン)_ｒ－ＮＲ^ｅＣＯＮＲ^ｆ－(Ｃ_１－６アルキレン)_ｓから選択され、ここで、Ｃ_１－６アルキレン、Ｃ_２－６アルケニレンおよびＣ_２－６アルキニレンの各々は、場合によりハロ、ＣＮ、ＮＯ_２、Ｎ_３、ＳＣＮ、ＯＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－８アルコキシアルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルコキシ、アミノ、Ｃ_]－６アルキルアミノおよびＣ_２._８ジアルキルアミノから独立して選択される１、２または３置換基で置換されていてよく；
Ｄ^３およびＥ^３は、独立して存在しないか、または独立してＣ_１－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２－６アルキニレン、アリーレン、シクロアルキレン、ヘテロアリーレンおよびヘテロシクロアルキレンから選択され、ここで、Ｃ_)－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２－６アルキニレン、アリーレン、シクロアルキレン、ヘテロアリーレンおよびヘテロシクロアルキレンの各々は、場合によりハロ、ＣＮ、ＮＯ_２、Ｎ_３、ＳＣＮ、ＯＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－８アルコキシアルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキル、アミノ、Ｃ_１－６アルキルアミノおよびＣ_２－８ジアルキルアミノから独立して選択される１、２または３置換基で置換されていてよく；
Ｄ^４およびＥ^４は、独立してＨ、ハロ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃ)_－４ハロアルキル、ハロスルファニル、Ｃ_１－４ヒドロキシアルキル、Ｃ_１－４シアノアルキル、Ｃｙ^１、ＣＮ、ＮＯ_２、または^ａ、ＳＲ^ａ、Ｃ(Ｏ)Ｒ^ｂ、Ｃ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｃ(Ｏ)ＯＲ^０、ＯＣ(Ｏ)Ｒ^６、ＯＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＲ^ｄ、ＮＲ℃(Ｏ)Ｒ^ｂ、ＮＲ^ｃＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^０Ｃ(Ｏ)ＯＲ^０、Ｃ(＝ＮＲ’)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(＝ＮＲ^ｉ)ＮＲ^ｃＲ^ｄ、Ｓ(Ｏ)Ｒ^ｂ、Ｓ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｓ(Ｏ)_２Ｒ^ｂ、ＮＲ^ｃＳ(Ｏ)_２Ｒ^ｂ、Ｃ(＝ＮＯＨ)Ｒ^ｂ、Ｃ(＝ＮＯ(Ｃｉ_－６アルキル)Ｒ^ｂおよびＳ(Ｏ)_２ＮＲ^ｃＲ^ｄから選択され、ここで、該Ｃ_１－８アルキル、Ｃ_２－８アルケニルまたはＣ_２－８アルキニルは、場合により、ハロ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、Ｃ_１－４ハロアルキル、ハロスルファニル、Ｃ_１－４ヒドロキシアルキル、Ｃ_１－４シアノアルキル、Ｃｙ^１、ＣＮ、ＮＯ_２、または^ａ、ＳＲ^ａ、Ｃ(Ｏ)Ｒ^ｂ、Ｃ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｃ(Ｏ)ＯＲ^ａ、ＯＣ(Ｏ)Ｒ^ｂ、ＯＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(Ｏ)Ｒ^ｂ、ＮＲ^ｃＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(Ｏ)ＯＲ^ａ、Ｃ(＝ＮＲ^ｉ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(＝ＮＲ’)ＮＲ^ｃＲ^ｄ、Ｓ(Ｏ)Ｒ^ｂ、Ｓ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｓ(Ｏ)_２Ｒ^６、ＮＲ^０Ｓ(Ｏ)_２Ｒ”、Ｃ(＝ＮＯＨ)Ｒ^ｂ、Ｃ(＝ＮＯ(Ｃ,._６アルキル))Ｒ^ｂおよびＳ(Ｏ)_２ＮＲ^ｃＲ^ｄから独立して選択される１、２、３、４、５または６置換基で置換されていてよく；
Ｒ^ａはＨ、Ｃｙ^１、－(Ｃ_１－６アルキル)－Ｃｙ^１、Ｃ_－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニルであり、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニルまたはＣ_２._６アルキニルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｂはＨ、Ｃｙ^１、－(Ｃ_１－６アルキル)－Ｃｙ’、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２._６アルケニル、Ｃ_２－６アルキニルであり、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２._６アルケニルまたはＣ_２._６アルキニルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ａ’およびＲ^ａ”は、独立してＨ、Ｃｉ_－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｂ’およびＲ^ｂ”は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｃおよびＲ^ｄは、独立してＨ、Ｃｙ^１、－(Ｃ_１－６アルキル)－Ｃｙ’、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニルまたはＣ_２－６アルキニル、は、場合によりＣｙ^１、－(Ｃ_１－６アルキル)－Ｃｙ’、ＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキルおよびハロスルファニルから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃおよびＲ^ｄは、それらが結合しているＮ原子と一体となって、場合によりＣｙ^１、－(Ｃ_１－６アルキル)－Ｃｙ^１、ＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルキルおよびハロスルファニルから独立して選択される１、２または３置換基で置換されていてよい４員、５員、６員または７員ヘテロシクロアルキル基を形成し；
Ｒ^ｃ’およびＲ^ｄ’は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃ’およびＲ^ｄ’は、それらが結合しているＮ原子と一体となって、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよい４員、５員、６員または７員ヘテロシクロアルキル基を形成し；
Ｒ^ｃ”およびＲ^ｄ”は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－_６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃ”およびＲ^ｄ”は、それらが結合しているＮ原子と一体となって、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ハロスルファニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキルおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよい４員、５員、６員または７員ヘテロシクロアルキル基を形成し；Ｒ
Ｒ^ｊはＨ、ＣＮ、ＮＯ_２またはＣ_１－６アルキルであり；
Ｒ^ｅおよびＲ^ｆは、独立してＨおよびＣ_１－６アルキルから選択され；
Ｒ^ｉはＨ、ＣＮまたはＮＯ_２であり；
ｍは０または１であり；
ｎは０または１であり；
ｐは０、１、２、３、４、５または６であり；
ｑは０、１、２、３、４、５または６であり；
ｒは０または１であり；
ｓは０または１である。〕
の化合物またはその薬学的に許容される塩もしくはプロドラッグである。 In some embodiments, the Janus kinase inhibitor is of formula (I) :.

[In the ceremony,
A ¹ and A ² are independently selected from C and N;
T, U and V are independently selected from O, S, N, CR ⁵ and NR ⁶ ; where the 5-membered ring formed by A ¹ , A ² , U, T and V is aromatic. can be;
X is N or CR ⁴ ;
Y is C _1-8 alkylene, C _2-8 alkenylene, C _2-8 ^alkinylene , (CR ¹¹ R ¹² ) p- (C _3-10 cycloalkylene)-(CR ¹¹ R I 2) _q , (CR ^lI R ¹² ) ) P- ( _Allylene )-(CR ¹¹ R ¹² ) _q , (CR ¹¹ R ¹² ) _p- (C _1-10 Heterocycloalkylene)-(CR ¹¹ R ¹² ) _q , (CR ¹¹ R ¹² ) p-( Heteroarylene)-(CR ^{11'R 12} ) _q , (CR ¹¹ R ¹² ) pO (CR ¹¹ R ¹² ), (CR ¹¹ R ¹² ) _p S (CR ¹¹ R ¹² ), (CR ¹¹ R ¹² ) _p C (O) (CR ¹¹ R ¹² ) _q , (CR ¹ (CR ^{1IR 12} ) _p C (O) NR ^c (CR ^I1 R ¹² ) _q , (CR ¹¹ R ^I2 ) _p C (O) O (CR ¹¹ ) R ^I2 ) _q , (CR ¹¹ R ¹² ) _p OC (O) (CR ¹¹ R ¹² ) _q , (CR ¹¹ R ^{I 2} ) _p NR ^c (CR ¹¹ R ^I 2) _p NR c (CR ¹¹ R ¹² ) _p NR ^c C (O) NR ^d (CR ¹¹ R ¹² ) _q , (CR ¹¹ R ¹² ) pS (O) (CR ¹¹ R ¹² ) _q , (CR "R ¹² ) _p S (O) NR ^c (CR ¹¹ R ¹² ) ) _Q , (CR ¹¹ R ¹² ) pS (O) ₂ (CR ¹¹ R ¹² ) _q or (CR ¹¹ R ¹² ) pS (O) ₂ NR ^c (CR ¹¹ R ¹² ) _q , where C _1-8 alkylene, _C2.8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene or heteroarylene are optionally selected independently of _-D' ^- D _{2 -} D ^{3 -} D4. May be substituted with 1, 2 or 3 substituents;
Z is H, halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Ci _-4 haloalkyl, halosulfanyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, = C-R. ^!! , = N-R ^! , Cy ¹ , CN, NO ₂ , OR, SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ³ , OC (O) R ⁶ , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^b , NR ^c C (O) NR ^c R ^d , NR ⁰ C (O) OR ³ , C (= NR') NR ^c R ^d , NR ^c C (= NR ⁱ ) NR ^c R ^d , S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b , C (= NOH) R ^b ,: 5 alkyl) R ^b and S (O) ₂ NR ^c R ^d , where the C _1-8 alkyl, C _2-8 alkenyl or C _2-8 alkynyl is optionally halo, C. _w Alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Ci _-4 haloalkyl, halosulfanyl, C _1-4 hydroxyalkyl, Ci _-4 cyanoalkyl, Cy ¹ , CN, NO ₂ , OR ", SR", C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ”, OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^b , NR ° C (O) NR ^c R ^d , NR ^c C (O) OR ^a , C (= NR ⁱ ) NR ^c R ^d , NR ^c C (= NR') NR ° R ^d , S (O) R ^b , S (O) NR ° R ^d , S (O) ₂ R ^b , ONR ^c S (O) ₂ R ^b , C (= NOH) R ^b , C (= NO (C _1-6 alkyl)) It may be substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from R ^b and S (O) ₂ NR ^c R ^d ; where Z is H and n is n. 1;
Or-(Y) _n ^- Z moieties are i) ^A2 , ii) T or ^V R5 or R6 and iii) T or ^V R5 or R6 to which the ^moiety is attached. Together with the existing C or N atom, it forms a 4- to 20-membered aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring fused with a 5-membered ring formed by A ¹ , A ² , U, T and V. Here, the 4- to 20-membered aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring is optionally selected independently of − (W) _m −Q with 1, 2, 3, 4 or 5 substitutions. May be substituted with a group;
W is C _1-8 alkyrenyl, C _2-8 alkenylenyl, C _2-8 alkynyl, O, S _, C (O), C (O) NR ^c' , C (O) O, OC (O), OC ( O) NR ^c' , NR ^{c' ,} NR c'C (O) NR ^d' , S (O), S (O) NR ^c' , S (O) ₂ or S (O) ₂ NR ^c' . ;
Q is H, halo, CN, NO ₂ , Ci- ₈ alkyl, C _2- S alkenyl, C _2-8 alkynyl, d. ₈ haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl. Here, the C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, Ci- ₈ haloalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be halo, C _1-4 alkyl, as the case may be. C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, halosulfanyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^3' , SR ^a' , C (O) R ^{b "} , C (O) NR ^{c'R d'} , C (O) OR ^3' , OC (O) R"^" , OC (O) NR ⁰ R"^" , NR ° R ^{d '} , NR ° ^' C (O) R ^b' , NR ^c'C (O) NR ° ^' R ^d' , NR ° ^' C (O) OR ^a' , S (O) R ^b' , S (O) NR c'R ^{d '} , S (O) ₂ R ^b> , NR ° ^' S (O) ₂ R ^b and S (O) ₂ NR ° ^' R ^d' selected independently 1, 2, 3 Or it may be substituted with a 4-substituted group;
Cy ¹ and Cy ² are independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, respectively, optionally halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C, respectively. _1-4 haloalkyl, halosulfanyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, CN, NO ₂ , 0R ^{a "} , SR ^a" , C (O) R ^{b "} , C (O) NR ^c" R ^{d "} , C (O) OR ^3" , OC (O) R ^{b "} , OC (O) NR ° ^" R ^{d "} , NR ^c" R ^{d "} , NR ^c" C (O) R ^{b "} , NR ^{c "} C (O) OR ^a" , NR ° ^" S (O) R ^b" , NR ° ^" S (O) ₂ R ^b" , S (O) R ^{b "} , S (O) NR ^c" R ^d , S (O) ₂ R ^{b " and} S (O) ₂ NR ° ^" R ^{d "} may be substituted with 1, 2, 3, 4 or 5 substituents independently selected;
R ¹ , R ² , R ³ and R ⁴ are independently H, halo, C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 haloalkyl, halosulfanyl, aryl, cyclo. Alkyne, Heteroaryl, Heterocycloalkyl, CN, NO ₂ , or ⁷ , SR ⁷ , C (O) R ⁸ , C (O) NR ⁹ R ¹⁰ , C (O) OR ⁷ OC (O) R ⁸ , OC (O) NR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NR ⁹ C (O) R ⁸ , NR ⁰ C (O) OR ⁷ , S (O) R ⁸ , S (O) NR ⁹ R ¹⁰ , S (O) ) ₂ R ⁸ and NR ⁹ S (O) ₂ R ⁸ and S (O) ₂ NR ⁹ R ¹⁰ ;
R5 is H, halo, C ₎ -4alkyl, ^C2-4alkenyl , _C2-4alkynyl , _CN4haloalkyl , ^{halosulfanyl, CN, NO2, or 7 ,} _{SR7 ,} C ⁽ O) R8, C (O) NR ⁹ R ¹⁰ , C (O) OR ⁷ , OC (O) R ⁸ , OC (O) NR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NR ⁹ C (O) R ⁸ , NR ⁹ C ( O) OR ⁷ , S (O) R ⁸ , S (O) NR ⁹ R ¹⁰ , S (O) ₂ R ⁸ , NR ⁹ S (O) ₂ R ⁸ or S (O) ₂ NR ⁹ R ¹⁰ . And;
R ⁶ is H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, or ⁷ , C (O) R ⁸ , C (O) NR ⁹ R ¹⁰ , C ( O) OR ⁷ , S (O) R ⁸ , S (O) NR ⁹ R ¹⁰ , S (O) ₂ R ⁸ or S (O) ₂ NR ⁹ R ¹⁰ ;
R ⁷ is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl. Alkyl or heterocycloalkylalkyl;
R ⁸ is H, C _1-6 alkyl, Ci _{- 6} haloalkyl, C _2-6 alkenyl, C _2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl. Or heterocycloalkylalkyl;
R ⁹ and R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2.6 alkynyl, C _1-6 alkyl carbonyl, _{aryl carbonyl, C 1-6 .} Selected from alkylsulfonyls, arylsulfonyls, aryls, heteroaryls, cycloalkyls, heterocycloalkyls, arylalkyls, heteroarylalkyls, cycloalkylalkyls and heterocycloalkylalkyls;
Alternatively, R ⁹ and R ¹⁰ combine with the N atom to which they are attached to form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group;
R ¹¹ and R ¹² are independently selected from H and -Ε ^ι -Ε ^2- Ε ³ -Ε ⁴ ;
D ¹ and E ¹ either do not exist independently or are independently selected from C _1-6 alkylene, C _2-6 alkenylene, C _{2.6 alkynylene} , arylene, cycloalkylene, heteroarylene and heterocycloalkylene. Where each of Ci _{- 6alkylene} , C _2-6 alkenylene, C _2.6 alkynylene, arylene, cycloalkylene, heteroarylene and heterocycloalkylene may be halo, CN, NO ₂ , N ₃ , SCN, respectively. Independent of OH, Ci. ₆ alkyl, C _1-6 haloalkyl, C _2.8 alkoxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, C _1-6 alkyl amino and C _2-8 dialkyl amino _. May be substituted with 1, 2 or 3 substituents selected in
D ² and E ² either do not exist independently or independently C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkinylene, (C _1-6 alkylene) _r -O- (C ₁ ). _-6alkylene ) _s , (C _1-6 alkylene) _r -S- (C _1-6 alkylene) _s , (C _1-6 alkylene) _r -NR ^e- (C _1-6 alkylene) _s , (C, . ₆ alkylene) _r -CO- (C _1-6 alkylene) _s , (C _1-6 alkylene) _r -COO- (C _1-6 alkylene) _s , (C _1-6 alkylene) _r -CONR ^e- ( C _1-6 alkylene) _s , (C _1-6 alkylene) _r -SO- (C _1-6 alkylene) _s , (C _1-6 alkylene) _r -SO _2- (C _1-6 alkylene) _s , ( Selected from C _1-6 alkylene) _r - ^{SONR c-} (C _1-6 alkylene) _s and (C _1-6 alkylene) _r -NR ^e CONR f- (C _1-6 alkylene) _s , where C Each of _1-6 alkylene, C _2-6 alkenylene and C _2-6 alkinylene may optionally be halo, CN, NO ₂ , N ₃ , SCN, OH, C _1-6 alkyl, C _1-6 haloalkyl, C ₂ Substituted with a 1, ₂ or 3 substituent independently selected from _-8 alkoxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, C _{] -6} alkylamino and _C2.8 dialkylamino. Well;
D ³ and E ³ either do not exist independently or are independently selected from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkinylene, arylene, cycloalkylene, heteroarylene and heterocycloalkylene. Where each of C _{) -6alkylene} , C _2-6 alkenylene, C _2-6 alkinylene, arylene, cycloalkylene, heteroarylene and heterocycloalkylene may be halo, CN, NO ₂ , N ₃ , SCN. , OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkoxyalkyl, C _1-6 alkoxy, C _1-6 haloalkyl, amino, C _1-6 alkyl amino and C _2-8 dialkyl amino May be substituted with an independently selected 1, 2 or 3 substituent;
D ⁴ and E ⁴ are independently H, halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C) _-4 haloalkyl, halosulfanyl, C _1-4 hydroxyalkyl, C _{1 -4} Cyanoalkyl, Cy ¹ , CN, NO ₂ , or ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ⁰ , OC (O) R ⁶ , OC (O) NR ^c R ^d , NR ^c R ^d , NR ° C (O) R ^b , NR ^c C (O) NR ^c R ^d , NR ⁰ C (O) OR ⁰ , C (= NR') NR ^c R ^d , NR ^c C (= NR ⁱ ) NR ^c R ^d , S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b , C (= NOH) R ^b , C (= NO (Ci- ₆ alkyl) R ^b and S (O) ₂ NR ^c R ^d , where the C _1-8 alkyl, C _2-8 alkenyl or C _2-8 alkynyl may be halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, halosulfanyl, C _1-4 hydroxyalkyl, C _1-4 cyano. Alkyl, Cy ¹ , CN, NO ₂ , or ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^b , NR ^c C (O) NR ^c R ^d , NR ^c C (O) OR ^a , C (= NR ⁱ ) NR ^c R ^d , NR ^c C (= NR') NR ^c R ^d , S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ⁶ , NR ⁰ S (O) ₂ R ”, C (= NOH) R ^b , C (= NO (C ,. ₆ alkyl)) R ^b and S (O) ₂ NR ^c R ^d with 1, 2, 3, 4, 5 or 6 substituents selected independently. May be replaced;
Ra is H, Cy ¹ ,-(C _1-6 alkyl) ^{-Cy 1} , C- ₆ haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, where the C _1-6 alkyl, C. _1-6 haloalkyl, C _2-6 alkenyl or C _2.6 alkynyl may optionally be OH, CN, amino, halo, C _{1-6 alkyl, C 1-6 haloalkyl} , halosulfanyl, aryl, arylalkyl, heteroaryl. , Heteroarylalkyl, cycloalkyl and may be substituted with 1, 2 or 3 substituents independently selected from heterocycloalkyl;
R ^b are H, Cy ¹ ,-(C _1-6 alkyl) _-Cy ', C _1-6 alkyl, C _1-6 haloalkyl, C _2.6 alkenyl, C _2-6 alkynyl, wherein said. C _{1-6 alkyl} , C _1-6 haloalkyl, C _2.6 alkenyl or C _2.6 alkynyl may optionally be OH, CN, amino, halo, C _{1-6 alkyl} , C _1-6 haloalkyl, halosulfanyl, It may be substituted with a 1, 2 or 3 substituent independently selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R ^{a'and Ra'are} independently H, Ci- _6alkyl , C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, aryl. Selected from alkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl. , Heteroaryl, Heterocycloalkyl, Arylalkyl, Heteroarylalkyl, Cycloalkylalkyl or Heterocycloalkylalkyl, optionally OH, CN, Amino, Halo, C _1-6 Alkyl, C _1-6 Haloalkyl, Halo Sulfanyl, It may be substituted with 1, 2 or 3 substituents independently selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R ^b'and R ^b'are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, It is selected from arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo. Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, halosulfanyl. , Aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and may be substituted with 1, 2 or 3 substituents independently selected;
R ^c and R ^d are independently H, Cy ¹ ,-(C _1-6 alkyl) -Cy', C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl. Selected from, where the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, are optionally Cy ¹ ,-(C _1-6 alkyl) -Cy'. , OH, CN, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl and may be substituted with 1, 2 or 3 substituents independently selected from halosulfanyl;
Alternatively, R ^c and R ^d , together with the N atom to which they are bonded, optionally Cy ¹ ,-(C _1-6 alkyl) -Cy ¹ , OH, CN, amino, halo, C _1- . Forming 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl groups optionally substituted with 1, 2 or 3-substituted groups independently selected from ₆ -alkyl, C _1-6 alkyl and halosulfanyl;
R ^c'and R ^d' are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Selected from arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, halosulfanyl. , Aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and may be substituted with 1, 2 or 3 substituents independently selected;
Alternatively, R ^c'and R ^d' are combined with the N atom to which they are attached, optionally OH, CN, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, halosulfanyl, aryl. , Arylalkyl, Heteroaryl, Heteroarylalkyl, Cycloalkyl and Heterocycloalkyl may be substituted with 1, 2 or 3 substituents independently selected 4-membered, 5-membered, 6-membered or 7-membered heterocyclo Form an alkyl group;
R ^{c "} and R ^d" are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, _Selected from arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, halosulfanyl. , Aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and may be substituted with 1, 2 or 3 substituents independently selected;
Or R ^{c "} and R ^d" together with the N atom to which they are bonded, optionally OH, CN, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, halosulfanyl, aryl. , Arylalkyl, Heteroaryl, Heteroarylalkyl, Cycloalkyl and Heterocycloalkyl may be substituted with 1, 2 or 3 substituents independently selected 4-membered, 5-membered, 6-membered or 7-membered heterocyclo Form an alkyl group; R
^Rj is H, CN, NO ₂ or C _1-6 alkyl;
^Re and R ^f are independently selected from H and C _1-6 alkyl;
Ri is H, CN or NO ₂ ^;
m is 0 or 1;
n is 0 or 1;
p is 0, 1, 2, 3, 4, 5 or 6;
q is 0, 1, 2, 3, 4, 5 or 6;
r is 0 or 1;
s is 0 or 1. ]
Or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the INC424 has the following structure:

In some embodiments, INC424 is (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile. To.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an FGF receptor inhibitor to use a cancer, eg, a cancer described herein (eg, eg). The cancers disclosed in Table 1) are treated. In some embodiments, the FGF receptor inhibitor is a publication cited in Table 1 (eg, BUW078) or Table 1, eg, International Patent Publication WO2009 / 141386 (eg, Formula (I) and Example 127) and the United States. It is disclosed in Patent Publication No. 2010/01056667. In some embodiments, the FGF receptor inhibitor, eg BUW078, is a publication provided in Table 1 or cited in Table 1, eg, International Patent Publication WO2009 / 141386 (eg, Formula (I) and Example 127). And have a structure (compound or general structure) as disclosed in US Patent Publication No. 2010/01050667. In some embodiments, the FGF receptor inhibitor is a publication cited in Table 1 (eg, BGJ398) or Table 1, eg, US 8,552,002 (eg, Example 145 or formula (I) of column 6). ). In some embodiments, the FGF receptor inhibitor, eg, BGJ398, is a publication provided in Table 1 or cited in Table 1, eg, US 8,552,002 (eg, Formula 145 or Column 6 formula (I). )) Has a structure (compound or general structure) as disclosed in. In some embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with BUW078 or BGJ398 to treat the cancers listed in Table 1, such as solid tumors, such as gastrointestinal / gastrointestinal cancer; or hematological cancer. ..

〔式中、
ＸはＮまたはＣＨであり；
Ｒ^１は水素、ハロゲン、アルキル、飽和ヘテロシクリルで置換されたアルキルであり、これは置換されていないかまたはアルキル、アミノ、モノ－置換アミノ(ここで、置換基は、アルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキルからなる群から選択される)、二置換アミノ(ここで、置換基は、アルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、アルコキシからなる群から選択される)、置換アルコキシ(ここで、置換基は、ハロおよびアルコキシからなる群から選択される)で置換されており；
Ｒ^２は水素、ハロゲン、アルキル、飽和ヘテロシクリルで置換されたアルキルであり、これはは置換されていないかまたはアルキル、アミノ、モノ－置換アミノ(ここで、置換基は、アルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキルからなる群から選択される)、二置換アミノ(ここで、置換基は、アルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、アルコキシからなる群から選択される)、置換アルコキシ(ここで、置換基は、ハロおよびアルコキシからなる群から選択される)で置換されており；
Ａはアリールまたはヘテロアリールであり；
Ｂはアリールまたはヘテロアリールであり；
Ｒ^Ａ１は水素または水素と異なる置換基であり；
Ｒ^Ａ２は直接結合またはアルカンジイルであり；
Ｒ^Ｂ１は水素または水素と異なる置換基であり；
Ｒは直接結合またはアミノカルボニルであり；
ｍは０～３から選択される整数であり；
ｎは０～５から選択される整数である。〕
の化合物またはその塩、溶媒和物、エステル、Ｎ－オキシドである。 In some embodiments, the FGF receptor inhibitor is formulated (I).

[In the ceremony,
X is N or CH;
R ¹ is an alkyl substituted with hydrogen, halogen, alkyl, saturated heterocyclyl, which is unsubstituted or alkyl, amino, mono-substituted amino (where the substituents are alkyl, aminoalkyl, alkylamino). Alkoxy, selected from the group consisting of dialkylaminoalkyl), disubstituted amino (where the substituent is selected from the group consisting of alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy), substituted alkoxy. (Here, the substituent is selected from the group consisting of halo and alkoxy);
R ² is an alkyl substituted with hydrogen, halogen, alkyl, saturated heterocyclyl, which is unsubstituted or alkyl, amino, mono-substituted amino (where the substituents are alkyl, aminoalkyl, alkyl). Aminoalkyl, selected from the group consisting of dialkylaminoalkyl), disubstituted amino (where the substituent is selected from the group consisting of alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy), substituted. Alkoxy (where the substituents are selected from the group consisting of halos and alkoxys) has been substituted;
A is aryl or heteroaryl;
B is aryl or heteroaryl;
^RA1 is hydrogen or a substituent different from hydrogen;
RA2 is a direct bond or ^alkanedyl ;
^RB1 is hydrogen or a substituent different from hydrogen;
R is a direct bond or aminocarbonyl;
m is an integer selected from 0 to 3;
n is an integer selected from 0 to 5. ]
Compound or salt thereof, solvate, ester, N-oxide.

In some embodiments, BUW078 has the following structure:

In some embodiments, BUW078 is 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide. ..

〔式中、ｎは０、１、２、３、４または５であり；
Ｘ、ＹおよびＺは、各々独立して、ＮまたはＣ－Ｒ^５から選択され、ここで、Ｘ、ＹおよびＺの少なくとも２がＮであり；および
Ｘ^１は酸素であり、
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、存在するならば、有機または無機部分から独立して選択され、ここで、無機部分は、特にハロ、特にクロロ、ヒドロキシル、シアノ、アゾ(Ｎ＝Ｎ＝Ｎ)、ニトロから選択され；
ここで、有機部分は、置換または非置換であり、リンカー、－Ｌ^１－を経て結合してよく、有機部分は、特に水素；低級脂肪族(特にＣ_１、Ｃ_２、Ｃ_３またはＣ_４脂肪族)、例えば低級アルキル、低級アルケニル、低級アルキニル；アミノ；グアニジノ；ヒドロキシグアニジノ；ホルムアミジノ；イソチオウレイド；ウレイド；メルカプト；Ｃ(Ｏ)Ｈまたは他のアシル；アシルオキシ；置換ヒドロキシ；カルボキシ；スルホ；スルファモイル；カルバモイル；置換または非置換環状基、例えば環状基(置換であれ非置換であれ)は、シクロアルキル、例えばシクロヘキシル、フェニル、ピロール、イミダゾール、ピラゾール、イソキサゾール、オキサゾール、チアゾール、ピリダジン、ピリミジン、ピラジン、ピリジル、インドール、イソインドール、インダゾール、プリン、インドリジジン、キノリン、イソキノリン、キナゾリン、プテリジン、キノリジジン、ピペリジル、ピペラジニル、ピロリジン、モルホリニルまたはチオモルホリニルから選択され、例えば、置換低級脂肪族または置換ヒドロキシは、このような置換または非置換環状基で置換されていてよく；
１、２、３、４または５鎖内原子(例えばＣ、Ｎ、ＯおよびＳから選択される)を有する－Ｌ^１－および所望により(ｉ)Ｃ_１、Ｃ_２、Ｃ_３またはＣ_４アルキル、例えば、場合により－Ｏ－、－Ｃ(Ｏ)－または－ＮＲ_ａ－結合で中断および／または終了していてよいアルキル基；－Ｏ－；－Ｓ－；－Ｃ(Ｏ)－；シクロプロピル(２鎖内原子を有すると見なす)およびこれらの化学的に適当な組み合わせ；および－ＮＲ^ａ－(ここで、Ｒ^ａは水素、ヒドロキシ、ヒドロカルビルオキシまたはヒドロカルビルであり、ヒドロカルビルは、場合により－Ｏ－または－ＮＨ－結合で中断されていてよく、例えば、脂肪族基(例えば、１～７、例えば１、２、３または４炭素原子を有する)、シクロアルキル、特にシクロヘキシル、シクロアルケニル、特にシクロヘキセニルまたは他の炭素環式基、例えばフェニルであってよい)；ここで、ヒドロカルビル部分は置換または非置換であり；
各Ｒ^４は同一または異なり、有機または無機部分から選択され、例えば、各Ｒ^４は同一または異なり、ハロゲン；ヒドロキシ；保護ヒドロキシ、例えばトリアルキルシリルヒドロキシ；アミノ；アミジノ；グアニジノ；ヒドロキシグアニジノ；ホルムアミジノ；イソチオウレイド；ウレイド；メルカプト；Ｃ(Ｏ)Ｈまたは他のアシル；アシルオキシ；カルボキシ；スルホ；スルファモイル；カルバモイル；シアノ；アゾ；ニトロ；場合により１以上のハロゲンおよび／またはヒドロキシ、保護ヒドロキシ、例えばトリアルキルシリルヒドロキシ、アミノ、アミジノ、グアニジノ、ヒドロキシグアニジノ、ホルムアミジノ、イソチオウレイド、ウレイド、メルカプト、Ｃ(Ｏ)Ｈまたは他のアシル、アシルオキシ、カルボキシ、スルホ、スルファモイル、カルバモイル、シアノ、アゾまたはニトロから選択される１または２官能基で置換されていてよいＣ_１－Ｃ_７脂肪族であり；前記ヒドロキシ基、アミノ基、アミジノ基、グアニジノ基、ヒドロキシグアニジノ基、ホルムアミジノ基、イソチオウレイド基、ウレイド基、メルカプト基、カルボキシ基、スルホ基、スルファモイル基およびカルバモイル基の全ては、続いて、所望により、少なくとも１ヘテロ原子を１以上のＣ_１－Ｃ_７脂肪族基で置換されていてよい。〕
を有するものまたはその塩、エステル、Ｎ－オキシドもしくはプロドラッグである。 In some embodiments, the FGF receptor inhibitor has the following structure:

[In the formula, n is 0, 1, 2, 3, 4 or 5;
X, Y and Z are each independently selected from N or CR ⁵ , where at least 2 of X, Y and Z are N; and X ¹ is oxygen.
R ¹ , R ² , R ³ and R ⁴ , if present, are selected independently of the organic or inorganic moieties, where the inorganic moieties are particularly halos, in particular chloro, hydroxyl, cyano, azo (N =). N = N), selected from nitro;
Here, the organic moiety is substituted or unsubstituted and may be attached via a linker, ^-L1- , and the organic moiety is particularly hydrogen; lower aliphatic (particularly C ₁ , C ₂ , C ₃ or C ₄ ). Aliphatic), such as lower alkyl, lower alkenyl, lower alkynyl; amino; guanidino; hydroxyguanidino; formamidino; isothioureido; ureido; mercapto; C (O) H or other acyl; acyloxy; substituted hydroxy; carboxy; sulfo; sulfamoyl. Carbamoyl; substituted or unsubstituted cyclic groups such as cyclic groups (substituted or unsubstituted) are cycloalkyls such as cyclohexyl, phenyl, pyrrole, imidazole, pyrazole, isoxazole, oxazole, thiazole, pyridazine, pyrimidine, pyrazine, Pyrimidines, indols, isoindoles, indazoles, purines, indolididines, quinoline, isoquinoline, quinazoline, pteridine, quinolididine, piperidyl, piperazinyl, pyrrolidine, morpholinyl or thiomorpholinyl, for example, substituted lower aliphatic or substituted hydroxy are such. May be substituted with substituted or unsubstituted cyclic groups;
-L1- with atoms in ¹ , 2, 3, 4 or 5 chains (eg selected from C, N, O and S) and optionally (i) C ₁ , C ₂ , C ₃ or C ₄ alkyl Alkyl groups that may be interrupted and / or terminated at the -O-, -C (O)-or -NR _a -bonds; -O-; -S-; -C (O)-; cyclo Propyl (considered to have atoms in two chains) and a chemically suitable combination thereof; and -NR ^a- (where ^Ra is hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, and hydrocarbyl is optionally- It may be interrupted by an O- or -NH- bond, eg, an aliphatic group (eg, having 1-7, eg, 1, 2, 3 or 4 carbon atoms), cycloalkyl, especially cyclohexyl, cycloalkenyl, especially. Cyclohexenyl or other carbocyclic group, eg phenyl); where the hydrocarbyl moiety is substituted or unsubstituted;
Each R ⁴ is the same or different, selected from organic or inorganic moieties, eg, each R ⁴ is the same or different, halogen; hydroxy; protected hydroxy, eg trialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino; formamizino. Isothioureide; ureido; mercapto; C (O) H or other acyl; acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; optionally one or more halogens and / or hydroxys, protected hydroxys such as trialkyl Selected from silylhydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureid, ureido, mercapto, C (O) H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo or nitro. It is _a C1 _- C7 aliphatic group that may be substituted with a 1 or 2 functional group; the hydroxy group, amino group, amidino group, guanidino group, hydroxyguanidino group, formamidino group, isothioureid group, ureido group, mercapto group. , The carboxy group, the sulfo group, the sulfamoyl group and the carbamoyl group may all be subsequently substituted with at least one heteroatom with _one or more C1 _- C7 aliphatic groups, if desired. ]
Or a salt, ester, N-oxide or prodrug thereof.

In some embodiments, X is CR ⁵ , R ⁵ is H; X 1 is oxygen; Y is N; Z is N; R ¹ is a substituted organic moiety, 4-ethylpiperazini. It is a cyclic group substituted with le (eg, phenyl), where -L ^1- is N ^Ra , where N ^Ra is H; R ² is an organic moiety (eg H); R ³ Is an organic moiety (eg, lower aliphatic, eg, methyl); ^R4 is chloro or methoxy; n is 4.

In some embodiments, the BGJ398 has the following structure:

In some embodiments, BGJ398 is a 3- (2,6-dichloro-3,5-dimethoxyphenyl) -1-(6-((4- (4-ethylpiperazine-1-yl) phenyl) amino) pyrimidine-4. -Il) -1-methylurea.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an EGF receptor inhibitor to use a cancer, eg, a cancer described herein (eg, eg). The cancers disclosed in Table 1) are treated. In some embodiments, the EGF receptor inhibitor is a publication cited in Table 1 (eg, EGF816) or Table 1, eg, WO 2013/184757 (eg, formula (5), claims 7, 10, 11 and 12). Alternatively, it is disclosed in Example 5). In some embodiments, the EGF receptor inhibitor, eg, EGF816, is a publication provided in Table 1 or cited in Table 1, eg, WO 2013/184757 (eg, formula (5), claims 7, 10, 11). And 12 or Example 5) having as disclosed in the structure (compound or general structure). In certain embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with EGF816 to produce the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treat.

In some embodiments, the EGF 816 is administered at an oral dose of about 50-500 mg, such as about 100 mg-400 mg, about 150 mg-350 mg or about 200 mg-300 mg, such as about 100 mg, 150 mg or 200 mg. The dosing schedule may change, for example, every other day to every day, twice or three times a day. In some embodiments, EGF816 is administered once daily at an oral dose of about 100-200 mg.

〔式中、
Ｗ^１およびＷ^２は、独立してＣＲ^１またはＮであり；
Ｒ^１、Ｒ^１’およびＲ^２は、独立して水素；ハロ；シアノ；Ｃ_１－６アルキル；Ｃ_１－６ハロアルキル；Ｎ、ＯおよびＳから選択される１～４ヘテロ原子を含む５～６員ヘテロアリール；フェニル、Ｎ、Ｏ、ＳおよびＰから選択される１～２ヘテロ原子を含み、場合によりオキソで置換されていてよい５～６員ヘテロシクリル；－Ｘ^１－Ｃ(Ｏ)ＯＲ^３；－Ｘ^１－Ｏ－Ｃ(Ｏ)Ｒ^３；－Ｘ^１－Ｃ(Ｏ)Ｒ^３；－Ｘ^１－Ｃ(Ｏ)ＮＲ^４Ｒ^５；－Ｘ^１－Ｃ(Ｏ)ＮＲ^４－Ｘ^３－Ｃ(Ｏ)ＯＲ^３；－Ｘ^１－Ｃ(Ｏ)ＮＲ^４－Ｘ^３－Ｓ(Ｏ)_０－２Ｒ^６；－Ｘ^１－ＮＲ^４Ｒ^５；－Ｘ^１ＮＲ^４－Ｘ^２－Ｃ(Ｏ)Ｒ^３；－Ｘ^１－ＮＲ^４－Ｘ^２－Ｃ(Ｏ)ＯＲ^３；－Ｘ^１－ＮＲ^４－Ｘ^２－Ｃ(Ｏ)ＮＲ^４Ｒ^５；－Ｘ^１－ＮＲ^４－Ｘ^３－Ｓ(Ｏ)_０－２Ｒ^６；－Ｘ^１－ＮＲ^４Ｓ(Ｏ)_２Ｒ^６；－Ｘ^１－ＯＳ(Ｏ)_２Ｒ^６；－Ｘ^１－ＯＲ^３；－Ｘ^１－Ｏ－Ｘ^４－ＯＲ^３；－Ｘ^１－Ｏ－Ｘ^４－Ｓ(Ｏ)_０－２Ｒ^６；－Ｘ^１－Ｏ－Ｘ^４－ＮＲ^４Ｒ^５；－Ｘ^１－Ｓ(Ｏ)_０－２Ｒ^６；－Ｘ^１－Ｓ(Ｏ)_０－２－Ｘ^３－ＮＲ^４Ｒ^５；－Ｘ^１－Ｃ(Ｏ)ＮＲ^４－Ｘ^３－Ｐ(Ｏ)Ｒ^６ａＲ^６ｂ；－Ｘ^１－ＮＲ^４－Ｘ^１－Ｐ(Ｏ)Ｒ^６ａＲ^６ｂ；－Ｘ^１－Ｏ－Ｘ^１－Ｐ(Ｏ)Ｒ^６ａＲ^６ｂ；－Ｘ^１－Ｐ(Ｏ)Ｒ^６ａ－Ｘ^１－ＮＲ^４Ｒ^５；－Ｘ^１－Ｐ(Ｏ)Ｒ^６ａＲ^６ｂまたは－Ｘ^１－Ｓ(Ｏ)_２ＮＲ^４Ｒ^５であり；ここで、Ｒ^１またはＲ^２の各フェニル、ヘテロアリールまたはヘテロシクリルは置換されていないかまたはＯＨ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから選択される１～３基で置換されており；
Ｒ^３、Ｒ^４およびＲ^５は、独立して水素、Ｃ_１－６アルキルまたはＣ_１－６ハロアルキルであるか；またはＮＲ^４Ｒ^５と一体となったＲ^４およびＲ^５Ｎは、Ｎ、Ｏ、ＳおよびＰから選択される１～２ヘテロ原子を含み、場合により１～４Ｒ^７で置換されていてよい４～７員環を形成でき；
Ｒ^６はＣ_１－６アルキルまたはＣ_１－６ハロアルキルであり；
Ｒ^６ａおよびＲ^６ｂは、独立してヒドロキシ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルコキシ、６～１０員単環式または二環式アリール；Ｎ、ＯおよびＳから選択される１～４ヘテロ原子を含む５～１０員ヘテロアリール；またはＮ、ＯおよびＳから選択される１～４ヘテロ原子を含み、場合によりオキソで置換されていてよい４～１２員単環式または二環式ヘテロシクリルであり；
Ｒ^８は

であり；
Ｘ^１およびＸ^２は、独立して結合またはＣ_１－６アルキルであり；
Ｘ^３はＣ_１－６アルキルであり；
Ｘ^４はＣ_２－６アルキルであり；
Ｒ^１２、Ｒ^１３、Ｒ^１６およびＲ^１７は、独立して水素またはＣ_１－６アルキルであり；
Ｒ^１４およびＲ^１５は、独立して水素；Ｃ_１－６アルキル；－Ｃ(Ｏ)Ｏ－(Ｃ_１－６アルキル)；非置換またはＣ_１－６アルキルで置換されたＣ_３－７シクロアルキルであるか；またはＲ^１４およびＲ^１５は、ＮＲ^１４Ｒ^１５のＮと一体となって、Ｎ、Ｏ、ＳおよびＰから選択される１～２ヘテロ原子を含み、場合により１～４Ｒ^１８基で置換されていてよい４～７員環を形成し；
Ｒ^７およびＲ^１８は、独立してオキソ、ハロ、ヒドロキシル、Ｃ_１－６アルキルまたはＣ_１－６アルコキシであり；
ｍおよびｑは、独立して１～２である。〕
のものまたはその薬学的に許容される塩である。 In some embodiments, the EGF receptor inhibitor is of the formula.

[In the ceremony,
W ¹ and W ² are independently CR ¹ or N;
R ¹ , R ^1'and R ² independently contain hydrogen; halo; cyano; C _1-6 alkyl; C _1-6 haloalkyl; 5 to 4 heteroatoms selected from N, O and S. 6-membered heteroaryl; 5-6-membered heterocyclyl containing 1-2 heteroatoms selected from phenyl, N, O, S and P and optionally substituted with oxo; -X1 ^- C (O) OR ³ ; -X ¹ -OC (O) R 3; -X ¹ -C (O) R ³ ; -X ¹ -C (O) NR ⁴ R ⁵ ; -X ¹ -C ⁽ O) NR ^4- X ³ -C (O) OR ³ ; -X ¹ -C (O) NR ⁴ -X ³ -S (O) _0-2 R ⁶ ; -X ¹ -NR ⁴ R ⁵ ; -X ¹ NR ⁴ -X ² -C (O) R ³ ; -X ¹ -NR ⁴ -X ² -C (O) OR ³ ; -X ¹ -NR ⁴ -X ² -C (O) NR ⁴ R ⁵ ; -X ¹ -NR ⁴ -X ³ -S (O) _0-2 R ⁶ ; -X ¹ -NR ⁴ S (O) ₂ R ⁶ ; -X ¹ -OS (O) ₂ R ⁶ ; -X ¹ -OR ³ ; -X ¹ -O-X ⁴ -OR ³ ; -X ¹ -O-X ⁴ -S (O) _0-2 R ⁶ ; -X ¹ -O-X ⁴ -NR ⁴ R ⁵ ; -X ¹ -S (O) ) _0-2 R ⁶ ; -X ¹ -S (O) _0-2 -X ³ -NR ⁴ R ⁵ ; -X ¹ -C (O) NR ⁴ -X ³ -P (O) R ^6a R ^6b ; -X ¹ -NR ⁴ -X ¹ -P (O) R ^6a R ^6b ; -X ¹ -O-X ¹ -P (O) R ^6a R ^6b ; -X ¹ -P (O) R ^6a -X ¹ -NR ⁴ R ⁵ ; -X ¹ -P (O) R ^6a R ^6b or -X ¹ -S (O) ₂ NR ⁴ R ⁵ ; where R ¹ or R ² phenyl, heteroaryl or Heterocyclyl is unsubstituted or substituted with 1-3 groups selected from OH, halo, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 haloalkoxy;
Are R ³ , R ⁴ and R ⁵ independently hydrogen, C _1-6 alkyl or C _1-6 haloalkyl; or R ⁴ and R ⁵ N integrated with NR ⁴ R ⁵ are N, It can form a 4- to 7-membered ring containing 1-2 heteroatoms selected from O, S and P and optionally substituted with ^1-4R7 ;
R6 is C ^1-6 _{alkyl or C 1-6 haloalkyl} ;
R ^6a and R ^6b are independently hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 6-10 member monocyclic or bicyclic aryl; A 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S; or a 1 to 4 heteroatom selected from N, O and S, optionally substituted with oxo. It is a 4- to 12-membered monocyclic or bicyclic heterocyclyl;
^R8 is

And;
X ¹ and X ² are independently bonded or C _1-6 alkyl;
X ³ is C _1-6 alkyl;
X ⁴ is C _2-6 alkyl;
R ¹² , R ¹³ , R ¹⁶ and R ¹⁷ are independently hydrogen or C _1-6 alkyl;
R ¹⁴ and R ¹⁵ are independently hydrogen; C _1-6 alkyl; -C (O) O- (C _1-6 alkyl); unsubstituted or C _1-6 alkyl substituted C _3-7 cyclo. Is it alkyl; or R ¹⁴ and R ¹⁵ together with N of NR ¹⁴ R ¹⁵ contain 1-2 heteroatoms selected from N, O, S and P, optionally 1-4 R ¹⁸ Form a 4- to 7-membered ring that may be substituted with a group;
R ⁷ and R ¹⁸ are independently oxo, halo, hydroxyl, C _1-6 alkyl or C _1-6 alkoxy;
m and q are 1 to 2 independently. ]
Or a pharmaceutically acceptable salt thereof.

In some embodiments, R ¹ and R ^1'are independently hydrogen; methyl; t-butyl; trifluoromethyl; methoxy; ethoxy; trifluoromethoxy; difluoromethoxy; fluoro; chloro; cyano; dimethylamino; methylsulfonyl; Dimethylphosphoryl; tetrazolyl; pyrrolyl; unsubstituted or methyl-substituted phenyl; or piperidinyl.

In some embodiments, R ² is hydrogen; chloro; methyl; trifluoromethyl; methoxy; isopropoxy; cyano; hydroxymethyl; methoxymethyl; ethoxymethyl; methylsulfonyl; methylcarbonyl; carboxy; methoxycarbonyl; carbamoyl; dimethylaminomethyl; Pyrrolidinylmethyl unsubstituted or substituted with 1-2 hydroxy, halo or methoxy; morpholinomethyl; azeditinylmethyl unsubstituted or substituted with 1-2 halo or methoxy; piperidinylmethyl; (((() 4-Methyl-3-oxo-piperazin-l-yl) methyl); ((4-acetylpiperazin-1-yl) methyl); (1,1-dioxidethiomorpholin-4-carbonyl); unsubstituted or 1 Pyrrolidinylcarbonyl substituted with ~ 2hydroxy; pyrrolidinylethoxy; (l, l-dioxidethiomorpholino) methyl; or unsubstituted or substituted with C _1-6 alkyl 1,2,4- Is it oxadiazolyl;
Alternatively, R ² may be -CH ₂ -N (CH ₃ ) -C (O) -CH ₃ ; -CH ₂ -O- (CH ₂ ) ₂ -OCH ₃ ; -CH ₂ -N (CH ₃ )-( CH ₂ ) ₂ -SO ₂ (CH ₃ ); -C (O) NH- (CH ₂ ) _{1.2 -} C (O) -OCH ₃ ; -C (O) NH- ₍ CH ₂ ) _1.2- C (O) OH; or -C (O) NH- (CH ₂ ) ₂ -SO ₂ (CH ₃ ).

であり；
ここで、Ｒ^１４およびＲ^１５は、独立して水素、Ｃ_１－６アルキルまたはＣ_３－７シクロアルキルであるか；またはＮＲ^１４Ｒ^１５においてＲ^１４およびＲ^１５はＮと一体となって、アゼチジニル、ピペリジル、ピロリジニルまたはモルホリニルを形成してよく；ここで、該アゼチジニルまたはピロリジニルは、場合により１～２ハロ、メトキシまたはヒドロキシルで置換されていてよく；
Ｒ^１２およびＲ^１３は、独立して水素、ハロ、シアノ、Ｃ_１－６アルキルまたはＣ_１－６ハロアルキルであり；
Ｒ^１６およびＲ^１７は、独立して水素またはＣ_１－６アルキルであるか；またはＲ^１６およびＲ^１７は、それらが結合している炭素と一体となって、Ｃ_３－６シクロアルキルを形成できる。 ^In some embodiments, the R8

And;
Here, R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl; or in NR ¹⁴ R ¹⁵ , R ¹⁴ and R ¹⁵ are integrated with N, Azetidinyl, piperidyl, pyrrolidinyl or morpholinyl may be formed; where the azetidinyl or pyrrolidinyl may be optionally substituted with 1-2 halos, methoxy or hydroxyl;
R ¹² and R ¹³ are independently hydrogen, halo, cyano, C _1-6 alkyl or C _1-6 halo alkyl;
Are R ¹⁶ and R ¹⁷ independently hydrogen or C _1-6 alkyl; or R ¹⁶ and R ¹⁷ combine with the carbon to which they are attached to form a C _3-6 cycloalkyl. can.

In some embodiments, W ¹ is CR ¹ ; W ² is N; R ¹ is methyl and R ^1'is hydrogen; R ² is chloro; m = 1; R ⁸ is partial structure. (H), q = 1; R ¹² , R ¹³ , R ¹⁶ and R ¹⁷ are hydrogen; R ¹⁴ and R ¹⁵ are methyl.

または

In some embodiments, the EGF receptor inhibitor has the following structure:

or

In some embodiments, the EGF 816 has the following structure:

In some embodiments, the EGF816 is (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl) -1H-benzo [d]. ] Imidazole-2-yl) -2-methylisonicotinamide.

In other embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a c-MET inhibitor to use a cancer, eg, a cancer described herein (eg, eg). , The cancers disclosed in Table 1) are treated. In some embodiments, the c-MET inhibitor is a publication cited in Table 1 (eg, INC280) or Table 1, eg, EP209447 (eg, claim 1 or 53) or US7,767,675 (eg, eg. It is disclosed in claim 4). In some embodiments, the c-MET inhibitor, eg, INC280, has a structure (compound or general structure) as disclosed in the publications provided in Table 1 or cited in Table 1. In certain embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with INC280 to include the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treats polymorphic glioblastoma (GBM), kidney cancer, liver cancer or gastric cancer. In some embodiments, the cancer has or is identified as having or having a c-MET mutation (eg, c-MET mutation or c-MET amplification).

In some embodiments, INC280 is administered at an oral dose of about 100-1000 mg, such as about 200 mg-900 mg, about 300 mg-800 mg or about 400 mg-700 mg, such as about 400 mg, 500 mg or 600 mg. The dosing schedule may change, for example, every other day to every day, twice or three times a day. In some embodiments, INC280 is administered twice daily at an oral dose of about 400-600 mg.

〔式中、
ＡはＮまたはＣＲ^３であり；
Ｃｙ^１はアリール、ヘテロアリール、シクロアルキルまたはヘテロシクロアルキルであり、各々場合により１、２、３、４または５―Ｗ－Ｘ－Ｙ－Ｚで置換されていてよく；
Ｃｙ^２はアリール、ヘテロアリール、シクロアルキルまたはヘテロシクロアルキルであり、各々場合により１、２、３、４または５－Ｗ’－Ｘ’－Ｙ’－Ｚ’で置換されていてよく；
Ｌ^１は(ＣＲ^４Ｒ^５)_ｍ、(ＣＲ^４Ｒ^５)_ｐ－(シクロアルキレン)－(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐ－(アリーレン)－(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐ－(ヘテロシクロアルキレン)－(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐ－(ヘテロアリーレン)－(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＯ(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＳ(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＣ(Ｏ)(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｓＣ(Ｏ)ＮＲ^６(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＣ(Ｏ)Ｏ(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＯＣ(Ｏ)(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＯＣ(Ｏ)ＮＲ^６(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＮＲ^６(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＮＲ^６Ｃ(Ｏ)ＮＲ^６(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＳ(Ｏ)(ＣＲ^４Ｒ^５)_ｑ、(ＣＲ^４Ｒ^５)_ｐＳ(Ｏ)ＮＲ^４(ＣＲ^５Ｒ^６)_ｑ、(ＣＲ^４Ｒ^５)_ｐＳ(Ｏ)_２(ＣＲ^４Ｒ^５)_ｑまたは(ＣＲ^４Ｒ^５)_ｐＳ(Ｏ)_２ＮＲ^６(ＣＲ^４Ｒ^５)_ｑであり、ここで、該シクロアルキレン、アリーレン、ヘテロシクロアルキレンまたはヘテロアリーレンは、場合によりＣｙ^３、ハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、Ｎ_３、または^ａ、ＳＲ^ａ、Ｃ(Ｏ)Ｒ^ｂ、Ｃ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｃ(Ｏ)ＯＲ^ａ、ＯＣ(Ｏ)Ｒ^ｂ、ＯＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(Ｏ)Ｒ^ｂ、ＮＲ^ｃＣ(Ｏ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(Ｏ)ＯＲ^ａ、Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ(＝ＮＲ^ｇ)ＮＲ^ｃＲ^ｄ、Ｐ(Ｒ^ｆ)_２、Ｐ(ＯＲ^ｅ)_２、Ｐ(Ｏ)Ｒ^ｅＲ^ｆ、Ｐ(Ｏ)ＯＲ^ｅＯＲ^ｆ、Ｓ(Ｏ)Ｒ^ｂ、Ｓ(Ｏ)ＮＲ^ｃＲ^ｄ、Ｓ(Ｏ)_２Ｒ^ｂ、ＮＲ^ｃＳ(Ｏ)_２Ｒ^ｂおよびＳ(Ｏ)_２ＮＲ^ｃＲ^ｄから独立して選択される１、２または３置換基で置換されていてよく；
Ｌ^２は(ＣＲ^７Ｒ^８)_ｒ、(ＣＲ^７Ｒ^８)_ｓ－(シクロアルキレン)－(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓ－(アリーレン)－(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓ－(ヘテロシクロアルキレン)－(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓ－(ヘテロアリーレン)－(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＯ(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＳ(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＣ(Ｏ)(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＣ(Ｏ)ＮＲ^９(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＣ(Ｏ)Ｏ(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＯＣ(Ｏ)(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＯＣ(Ｏ)ＮＲ^９(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)、ＮＲ^９(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＮＲ^９Ｃ(Ｏ)ＮＲ^９(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＳ(Ｏ)(ＣＲ^７Ｒ^８)_ｔ、(ＣＲ^７Ｒ^８)_ｓＳ(Ｏ)ＮＲ^７(ＣＲ^８Ｒ^９)_ｔ、(ＣＲ^７Ｒ^８)_ｓＳ(Ｏ)_２(ＣＲ^７Ｒ^８)_ｔまたは(ＣＲ^７Ｒ^８)_ｓＳ(Ｏ)_２ＮＲ^９(ＣＲ^７Ｒ^８)_ｔであり、ここで、該シクロアルキレン、アリーレン、ヘテロシクロアルキレンまたはヘテロアリーレンは、場合によりＣｙ^４、ハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、Ｎ_３、または^ａ１、ＳＲ^ａ１、Ｃ(Ｏ)Ｒ^ｂ１、Ｃ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、Ｃ(Ｏ)ＯＲ^ａ１、ＯＣ(Ｏ)Ｒ^ｂ１、ＯＣ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ(Ｏ)Ｒ^ｂ１、ＮＲ^ｃ１Ｃ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ(Ｏ)ＯＲ^ａ１、Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ１Ｒ^ｄ１、Ｐ(Ｒ^ｆ１)_２、Ｐ(ＯＲ^ｅ１)_２、Ｐ(Ｏ)Ｒ^ｅ１Ｒ^ｆ１、Ｐ(Ｏ)ＯＲ^ｅ１ＯＲ^ｆ１、Ｓ(Ｏ)Ｒ^ｂ１、Ｓ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、Ｓ(Ｏ)_２Ｒ^ｂ１、ＮＲ^ｃ１Ｓ(Ｏ)_２Ｒ^ｂ１およびＳ(Ｏ)_２ＮＲ^ｃ１Ｒ^ｄ１から独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^１はＨまたは―Ｗ”－Ｘ”－Ｙ”－Ｚ”であり；
Ｒ^２はＨ、ハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ＣＮ、ＮＯ_２、または^Ａ、ＳＲ^Ａ、Ｃ(Ｏ)Ｒ^Ｂ、Ｃ(Ｏ)ＮＲ^ＣＲ^Ｄ、Ｃ(Ｏ)ＯＲ^Ａ、ＯＣ(Ｏ)Ｒ^Ｂ、ＯＣ(Ｏ)ＮＲ^ＣＲ^Ｄ、ＮＲ^ＣＲ^Ｄ、ＮＲ^ＣＣ(Ｏ)Ｒ^ＢＮＲ^ＣＣ(Ｏ)ＮＲ^ＣＲ^Ｄ、ＮＲ^ＣＣ(Ｏ)ＯＲ^Ａ、Ｓ(Ｏ)Ｒ^Ｂ、Ｓ(Ｏ)ＮＲ^ＣＲ^Ｄ、Ｓ(Ｏ)_２Ｒ^Ｂ、ＮＲ^ＣＳ(Ｏ)_２Ｒ^ＢまたはＳ(Ｏ)_２ＮＲ^ＣＲ^Ｄであり；
Ｒ^３はＨ、シクロアルキル、アリール、ヘテロシクロアルキル、ヘテロアリール、ハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ＣＮ、ＮＯ_２、または^Ａ、ＳＲ^Ａ、Ｃ(Ｏ)Ｒ^Ｂ、Ｃ(Ｏ)ＮＲ^ＣＲ^Ｄ、Ｃ(Ｏ)ＯＲ^Ａ、ＯＣ(Ｏ)Ｒ^Ｂ、ＯＣ(Ｏ)ＮＲ^ＣＲ^Ｄ、ＮＲ^ＣＲ^Ｄ、ＮＲ^ＣＣ(Ｏ)Ｒ^Ｂ、ＮＲ^ＣＣ(Ｏ)ＮＲ^ＣＲ^Ｄ、ＮＲ^ＣＣ(Ｏ)ＯＲ^Ａ、Ｓ(Ｏ)Ｒ^Ｂ、Ｓ(Ｏ)ＮＲ^ＣＲ^Ｄ、Ｓ(Ｏ)_２Ｒ^Ｂ、ＮＲ^ＣＳ(Ｏ)_２Ｒ^ＢおよびＳ(Ｏ)_２ＮＲ^ＣＲ^Ｄであり；ここで、該シクロアルキル、アリール、ヘテロシクロアルキル、ヘテロアリールまたはＣ_１－６アルキルは、場合によりＣｙ^５、ハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、Ｎ_３、または^ａ１、ＳＲ^ａ１、Ｃ(Ｏ)Ｒ^ｂ１、Ｃ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、Ｃ(Ｏ)ＯＲ^ａ１、ＯＣ(Ｏ)Ｒ^ｂ１、ＯＣ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ(Ｏ)Ｒ^ｂ１、ＮＲ^ｃ１Ｃ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ(Ｏ)ＯＲ^ａ１、Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ１Ｒ^ｄ１、Ｐ(Ｒ^ｆ１)_２、Ｐ(ＯＲ^ｅ１)_２、Ｐ(Ｏ)Ｒ^ｅ１Ｒ^ｆ１、Ｐ(Ｏ)ＯＲ^ｅ１ＯＲ^ｆ１、Ｓ(Ｏ)Ｒ^ｂ１、Ｓ(Ｏ)ＮＲ^ｃ１Ｒ^ｄ１、Ｓ(Ｏ)_２Ｒ^ｂ１、ＮＲ^ｃ１Ｓ(Ｏ)_２Ｒ^ｂ１およびＳ(Ｏ)_２ＮＲ^ｃ１Ｒ^ｄ１から独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^２および―Ｌ^２－Ｃｙ^２は、連結して、式

の基を形成し、
ここで、環Ｂは縮合アリールまたは縮合ヘテロアリール環であり、各々場合により１、２または３－Ｗ’－Ｘ’－Ｙ’－Ｚ’で置換されていてよく；
Ｒ^４およびＲ^５は、独立してＨ、ハロ、ＯＨ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６アルコキシ、アルコキシアルキル、シアノアルキル、ヘテロシクロアルキル、シクロアルキル、Ｃ_１－６ハロアルキル、ＣＮおよびＮＯ_２から選択され；
Ｒ^７およびＲ^８は、独立してＨ、ハロ、ＯＨ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキル、ＣＮおよびＮＯ_２から選択され；
またはＲ^７およびＲ^８は、それらが結合しているＣ原子と一体となって、３員、４員、５員、６員または７員シクロアルキルまたはヘテロシクロアルキル環を形成し、各々場合によりハロ、ＯＨ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキル、ＣＮおよびＮＯ_２から独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^９はＨ、Ｃ_１－６アルキル、Ｃ_２－６アルケニルまたはＣ_２－６アルキニルであり；
Ｗ、Ｗ’およびＷ”は、独立して存在しないか、または独立してＣ_１－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２－６アルキニレン、Ｏ、Ｓ、ＮＲ^ｈ、ＣＯ、ＣＯＯ、ＣＯＮＲ^ｈ、ＳＯ、ＳＯ_２、ＳＯＮＲ^ｈおよびＮＲ^ｈＣＯＮＲ^ｉから選択され、ここで、Ｃ_１－６アルキレン、Ｃ_２－６アルケニレンおよびＣ_２－６アルキニレンの各々は、場合によりハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ＯＨ、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルコキシ、アミノ、Ｃ_１－６アルキルアミノおよびＣ_２－８ジアルキルアミノから独立して選択される１、２または３置換基で置換されていてよく；
Ｘ、Ｘ’およびＸ”は、独立して存在しないか、または独立してＣ_１－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２－６アルキニレン、アリーレン、シクロアルキレン、ヘテロアリーレンおよびヘテロシクロアルキレンから選択され、ここで、Ｃ_１－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２－６アルキニレン、アリーレン、シクロアルキレン、ヘテロアリーレンおよびヘテロシクロアルキレンの各々は、場合によりハロ、ＣＮ、ＮＯ_２、ＯＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－８アルコキシアルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルコキシ、Ｃ_２－８アルコキシアルコキシ、シクロアルキル、ヘテロシクロアルキル、Ｃ(Ｏ)ＯＲ^ｊ、Ｃ(Ｏ)ＮＲ^ｈＲ^ｉ、アミノ、Ｃ_１－６アルキルアミノおよびＣ_２－８ジアルキルアミノから独立して選択される１、２または３置換基で置換されていてよく；
Ｙ、Ｙ’およびＹ”は、独立して存在しないか、または独立してＣ_１－６アルキレン、Ｃ_２－６アルケニレン、Ｃ_２－６アルキニレン、Ｏ、Ｓ、ＮＲ^ｈ、ＣＯ、ＣＯＯ、ＣＯＮＲ^ｈ、ＳＯ、ＳＯ_２、ＳＯＮＲ^ｈおよびＮＲ^ｈＣＯＮＲ^ｉから選択され、ここで、Ｃ_１－６アルキレン、Ｃ_２－６アルケニレンおよびＣ_２－６アルキニレンの各々は、場合によりハロ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、ＯＨ、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルコキシ、アミノ、Ｃ_１－６アルキルアミノおよびＣ_２－８ジアルキルアミノから独立して選択される１、２または３置換基で置換されていてよく；
Ｚ、Ｚ’およびＺ”は、独立してＨ、ハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、Ｎ_３、または^ａ２、ＳＲ^ａ２、Ｃ(Ｏ)Ｒ^ｂ２、Ｃ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、Ｃ(Ｏ)ＯＲ^ａ２、ＯＣ(Ｏ)Ｒ^ｂ２、ＯＣ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ(Ｏ)Ｒ^ｂ２、ＮＲ^ｃ２Ｃ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ(Ｏ)ＯＲ^ａ２、Ｃ(＝ＮＲ^９)ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ２Ｒ^ｄ２、Ｐ(Ｒ^ｆ２)_２、Ｐ(ＯＲ^ｅ２)_２、Ｐ(Ｏ)Ｒ^ｅ２Ｒ^ｆ２、Ｐ(Ｏ)ＯＲ^ｅ２ＯＲ^ｆ２、Ｓ(Ｏ)Ｒ^ｂ２、Ｓ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、Ｓ(Ｏ)_２Ｒ^ｂ２、ＮＲ^ｃ２Ｓ(Ｏ)_２Ｒ^ｂ２、Ｓ(Ｏ)_２ＮＲ^ｃ２Ｒ^ｄ２、アリール、シクロアルキル、ヘテロアリールおよびヘテロシクロアルキルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリールおよびヘテロシクロアルキルは、場合によりハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、Ｎ_３、または^ａ２、ＳＲ^ａ２、Ｃ(Ｏ)Ｒ^ｂ２、Ｃ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、Ｃ(Ｏ)ＯＲ^ａ２、ＯＣ(Ｏ)Ｒ^ｂ２、ＯＣ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ(Ｏ)Ｒ^ｂ２、ＮＲ^ｃ２Ｃ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ(Ｏ)ＯＲ^ａ２、Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ２Ｒ^ｄ２、Ｐ(Ｒ^ｆ２)_２、Ｐ(ＯＲ^ｅ２)_２、Ｐ(Ｏ)Ｒ^ｅ２Ｒ^ｆ２、Ｐ(Ｏ)ＯＲ^ｅ２ＯＲ^ｆ２、Ｓ(Ｏ)Ｒ^ｂ２、Ｓ(Ｏ)ＮＲ^ｃ２Ｒ^ｄ２、Ｓ(Ｏ)_２Ｒ^ｂ２、ＮＲ^ｃ２Ｓ(Ｏ)_２Ｒ^ｂ２およびＳ(Ｏ)_２ＮＲ^ｃ２Ｒ^ｄ２から独立して選択される１、２、３、４または５置換基で置換されていてよく；
ここで、２つの隣接する―Ｗ－Ｘ－Ｙ－Ｚは、それらが結合している原子と一体となって、場合により縮合４～２０員シクロアルキル環または縮合４～２０員ヘテロシクロアルキル環を形成してよく、各々場合によりハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、または^ａ３、ＳＲ^ａ３、Ｃ(Ｏ)Ｒ^ｂ３、Ｃ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、Ｃ(Ｏ)ＯＲ^ａ３、ＯＣ(Ｏ)Ｒ^ｂ３、ＯＣ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｃ(Ｏ)Ｒ^ｂ３、ＮＲ^ｃ３Ｃ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｃ(Ｏ)ＯＲ^ａ３、Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ３Ｒ^ｄ３、Ｓ(Ｏ)Ｒ^ｂ３、Ｓ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、Ｓ(Ｏ)_２Ｒ^ｂ３、ＮＲ^ｃ３Ｓ(Ｏ)_２Ｒ^ｂ３、Ｓ(Ｏ)_２ＮＲ^ｃ３Ｒ^ｄ３、アリール、シクロアルキル、ヘテロアリールおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
ここで、２つの隣接する―Ｗ’－Ｘ’－Ｙ’－Ｚ’は、それらが結合している原子と一体となって、場合により、縮合４～２０員シクロアルキル環または縮合４～２０員ヘテロシクロアルキル環を形成してよく、各々、場合によりハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、または^ａ３、ＳＲ^ａ３、Ｃ(Ｏ)Ｒ^ｂ３、Ｃ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、Ｃ(Ｏ)ＯＲ^ａ３、ＯＣ(Ｏ)Ｒ^ｂ３、ＯＣ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｃ(Ｏ)Ｒ^ｂ３、ＮＲ^ｃ３Ｃ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｃ(Ｏ)ＯＲ^ａ３、Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ３Ｒ^ｄ３、ＮＲ^ｃ３Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ３Ｒ^ｄ３、Ｓ(Ｏ)Ｒ^ｂ３、Ｓ(Ｏ)ＮＲ^ｃ３Ｒ^ｄ３、Ｓ(Ｏ)_２Ｒ^ｂ３ _’ＮＲ^ｃ３Ｓ(Ｏ)_２Ｒ^ｂ３、Ｓ(Ｏ)_２ＮＲ^ｃ３Ｒ^ｄ３、アリール、シクロアルキル、ヘテロアリールおよびヘテロシクロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｃｙ^４およびＣｙ^５は、独立してアリール、シクロアルキル、ヘテロアリールおよびヘテロシクロアルキルから選択され、おのおの、場合によりハロ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、ハロスルファニル、ＣＮ、ＮＯ_２、Ｎ_３、または^ａ４、ＳＲ^ａ４、Ｃ(Ｏ)Ｒ^ｂ４、Ｃ(Ｏ)ＮＲ^ｃ４Ｒ^ｄ４、Ｃ(Ｏ)ＯＲ^ａ４、ＯＣ(Ｏ)Ｒ^ｂ４、ＯＣ(Ｏ)ＮＲ^ｃ４Ｒ^ｄ４、ＮＲ^ｃ４Ｒ^ｄ４、ＮＲ^ｃ４Ｃ(Ｏ)Ｒ^ｂ４、ＮＲ^ｃ４Ｃ(Ｏ)ＮＲ^ｃ４Ｒ^ｄ４、ＮＲ^ｃ４Ｃ(Ｏ)ＯＲ^ａ４、Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ４Ｒ^ｄ４、ＮＲ^ｃ４Ｃ(＝ＮＲ^ｇ)ＮＲ^ｃ４Ｒ^ｄ４、Ｐ(Ｒ^ｆ４)_２、Ｐ(ＯＲ^４)_２、Ｐ(Ｏ)Ｒ^ｅ４Ｒ^ｆ４、Ｐ(Ｏ)ＯＲ^ｅ４ＯＲ^ｆ４、Ｓ(Ｏ)^ｂ４ Ｓ(Ｏ)ＮＲ^ｃ４Ｒ^ｄ４、Ｓ(Ｏ)_２Ｒ^ｂ４、ＮＲ^ｃ４Ｓ(Ｏ)_２Ｒ^ｂ４およびＳ(Ｏ)_２ＮＲ^ｃ４Ｒ^ｄ４から独立して選択される１、２、３、４または５置換基で置換されていてよく；
Ｒ^ＡはＨ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリールであり、ここで、該Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリールは、場合によりＯＨ、ＣＮ、アミノ、ハロおよびＣ_１－４アルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ＢはＨ、Ｃ_１－４アルキル、Ｃ_２－４アルケニル、Ｃ_２－４アルキニル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリールであり、ここで、該Ｃ_１－４アルキル、Ｃ_２－４アルケニルまたはＣ_２－４アルキニル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリールは、場合によりＯＨ、ＣＮ、アミノ、ハロおよびＣ_１－４アルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ＣおよびＲ^Ｄは、独立してＨ、Ｃ_１－４アルキル、Ｃ_２－４アルケニルまたはＣ_２－４アルキニルから選択され、ここで、該Ｃ_１－４アルキル、Ｃ_２－４アルケニルまたはＣ_２－４アルキニル、は、場合によりＯＨ、ＣＮ、アミノ、ハロおよびＣ_１－４アルキルから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ＣおよびＲ^Ｄは、それらが結合しているＮ原子と一体となって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、各々、場合によりＯＨ、ＣＮ、アミノ、ハロおよびＣ_１－４アルキルから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ａ、Ｒ^ａ１、Ｒ^ａ２、Ｒ^ａ３およびＲ^ａ４は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－_６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｂ、Ｒ^ｂ１、Ｒ^ｂ２、Ｒ^ｂ３およびＲ^ｂ４は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｃおよびＲ^ｄは、独立してＨ、Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルキルから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃおよびＲ^ｄは、それらが結合しているＮ原子と一体となって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、各々、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｃ１およびＲ^ｄ１は、独立してＨ、Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃ１およびＲ^ｄ１は、それらが結合しているＮ原子と一体となって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、各々、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｃ２およびＲ^ｄ２は、独立してＨ、Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、アリールシクロアルキル、アリールヘテロシクロアルキル、アリールヘテロアリール、ビアリール、ヘテロアリールシクロアルキル、ヘテロアリールヘテロシクロアルキル、ヘテロアリールアリールおよびビヘテロアリールから選択され、ここで、該Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、アリールシクロアルキル、アリールヘテロシクロアルキル、アリールヘテロアリール、ビアリール、ヘテロアリールシクロアルキル、ヘテロアリールヘテロシクロアルキル、ヘテロアリールアリールおよびビヘテロアリールは、各々、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルコキシ、ヒドロキシアルキル、シアノアルキル、アリール、ヘテロアリール、Ｃ(Ｏ)ＯＲ^ａ４、Ｃ(Ｏ)Ｒ^ｂ４、Ｓ(Ｏ)_２Ｒ^ｂ３、アルコキシアルキルおよびアルコキシアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃ２およびＲ^ｄ２は、それらが結合しているＮ原子と一体となって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、各々、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルコキシ、ヒドロキシアルキル、シアノアルキル、アリール、ヘテロアリール、Ｃ(Ｏ)ＯＲ^ａ４、Ｃ(Ｏ)Ｒ^ｂ４、Ｓ(Ｏ)_２Ｒ^ｂ３、アルコキシアルキルおよびアルコキシアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｃ３およびＲ^ｄ３は、独立してＨ、Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃ３およびＲ^ｄ３は、それらが結合しているＮ原子と一体となって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、各々、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｃ４およびＲ^ｄ４は、独立してＨ、Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルから選択され、ここで、該Ｃ_１－１０アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
またはＲ^ｃ４およびＲ^ｄ４は、それらが結合しているＮ原子と一体となって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、各々、場合によりＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキルおよびＣ_１－６ハロアルコキシから独立して選択される１、２または３置換基で置換されていてよく；
Ｒ^ｅ、Ｒ^ｅ１、Ｒ^ｅ２およびＲ^ｅ４は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、(Ｃ_１－６アルコキシ)－Ｃ_１－６アルキル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、シクロアルキルアルキル、ヘテロアリールアルキルおよびヘテロシクロアルキルアルキルから選択され；
Ｒ^ｆ、Ｒ^ｆ１、Ｒ^ｆ２およびＲ^ｆ４は、独立してＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリールおよびヘテロシクロアルキルから選択され；
Ｒ^ｇはＨ、ＣＮおよびＮＯ_２であり；
Ｒ^ｈおよびＲ^ｉは、独立してＨおよびＣ_１－６アルキルから選択され；
Ｒ^ｊはＨ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルであり；
ｍは０、１、２、３、４、５または６であり；
ｐは０、１、２、３または４であり；
ｑは０、１、２、３または４であり；
ｒは０、１、２、３、４、５または６であり；
ｓは０、１、２、３または４であり；
ｔは０、１、２、３または４であり；
ただし、ＡがＣＨであるならば、Ｌ１はＣＯまたは(ＣＲ^４Ｒ^５)_ｕ(ここで、ｕは１である)以外である。〕
を有するものまたはその薬学的に許容される塩もしくはプロドラッグである。 In some embodiments, the c-MET inhibitor has the following structure:

[In the ceremony,
A is N or CR ³ ;
Cy ¹ is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, which may be optionally substituted with 1, 2, 3, 4 or 5-W-X-Y-Z;
Cy ² is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5-W'-X'-Y'-Z';
L ¹ is (CR ⁴ R ⁵ ) _m , (CR ⁴ R ⁵ ) _p- (cycloalkylene)-(CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p- (allylene)-(CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p- (heterocycloalkylene)-(CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p- (hetero allylene)-(CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) ) _p O (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p S (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p C (O) (CR ⁴ R ⁵ ) _q , (CR ⁴ R 5) ⁵ ) _s C (O) NR ⁶ (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p C (O) O (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p OC (O) (CR) ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p OC (O) NR ⁶ (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p NR ⁶ (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p NR ⁶ C (O) NR ⁶ (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p S (O) (CR ⁴ R ⁵ ) _q , (CR ⁴ R ⁵ ) _p S (O) NR ⁴ ( CR ⁵ R ⁶ ) _q , (CR ⁴ R ⁵ ) _p S (O) ₂ (CR ⁴ R ⁵ ) _q or (CR ⁴ R ⁵ ) _p S (O) ₂ NR ⁶ (CR ⁴ R ⁵ ) _q Where the cycloalkylene, arylene, heterocycloalkylene or heteroarylene is optionally Cy ³ , halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, halo. Sulfanyl, CN, NO ₂ , N ₃ , or ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^b , NR ^c C (O) NR ^c R ^d , NR ^c C (O) OR ^a , C (= NR ^g ) NR ^c R ^d , NR ^c C (= NR ^g ) NR ^c R ^d , P (R ^f ) ₂ , P (OR ^e ) ₂ , P (O) R ^e R ^f , P (O) OR ^e OR ^f , S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d , independently selected 1, 2 or May be substituted with 3 substituents;
L ² is (CR ⁷ R ⁸ ) _r , (CR ⁷ R ⁸ ) _s- (cycloalkylene)-(CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s- (Allylene)-(CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s- (heterocycloalkylene)-(CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s- (heteroallylen)-(CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) ) _s O (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s S (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s C (O) (CR ⁷ R ⁸ ) _t , (CR ⁷ R 8) ⁸ ) _s C (O) NR ⁹ (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s C (O) O (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s OC (O) (CR) ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s OC (O) NR ⁹ (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ), NR ⁹ (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s NR ⁹ C (O) NR ⁹ (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s S (O) (CR ⁷ R ⁸ ) _t , (CR ⁷ R ⁸ ) _s S (O) NR ⁷ ( CR ⁸ R ⁹ ) _t , (CR ⁷ R ⁸ ) _s S (O) ₂ (CR ⁷ R ⁸ ) _t or (CR ⁷ R ⁸ ) _s S (O) ₂ NR ⁹ (CR ⁷ R ⁸ ) _t . Here, the cycloalkylene, arylene, heterocycloalkylene or heteroarylene may optionally be Cy ⁴ , halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, halo. Sulfanyl, CN, NO ₂ , N ₃ , or ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , C (= NR ^g ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^g ) NR ^c1 R ^d1 , P (R ^f1 ) ₂ , P (OR ^e1 ) ₂ , P (O) R ^e1 R ^f1 , P (O) OR ^e1 OR ^f1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) It may be substituted with 1, 2 or 3 substituents independently selected from ₂ NR ^c1 R ^d1 ;
R ¹ is H or -W "-X" -Y "-Z";
R ² is H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , or ^A , SR ^A , C (O) R ^B , C (O) NR ^C R ^D , C (O) OR ^A , OC (O) R ^B , OC (O) NR ^C R ^D , N R ^C R ^D , NRC ^C (O) R ^B N R ^C C (O) NR ^C R ^D , NR ^{C C} (O) OR ^A , S (O) RB, S (O) NR ^{C R D ,} S (O) ₂ RB, NR ^C S (O) ₂ ^RB or S ( O) ₂ ^{NR CRD} ;
R ³ is H, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ or ^A. , SR ^A , ^C (O) RB, ^C (O) NR CRD, ^C (O) OR ^A , OC (O) RB, OC (O) ^{NR CRD} , ^{NRC R D} , ^NRC C (O) RB, NR ^C C (O) NR ^C R ^D , NR ^{C C} (O) OR ^A , S (O) RB, S (O) NR ^{C R D} , ^S (O) ₂ RB , NR ^C S (O) ₂ ^RB and S (O) ₂ NR ^CRD ; where the cycloalkyl, aryl, heterocycloalkyl, heteroaryl or ^C _1-6 alkyl are optionally Cy ⁵ , Halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, halosulfanyl, CN, NO ₂ , N ₃ , or ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , C (= NR ^g ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^g ) NR ^c1 R ^d1 , P (R ^f1 ) ₂ , P ( OR ^e1 ) ₂ , P (O) R ^e1 R ^f1 , P (O) OR ^e1 OR ^f1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 may be substituted with 1, 2 or 3 substituents independently selected;
Or R ² and -L ² -Cy ² are concatenated and the formula

Forming the basis of
Here, ring B is a condensed aryl or fused heteroaryl ring, which may be optionally substituted with 1, 2 or 3-W'-X'-Y'-Z', respectively;
R ⁴ and R ⁵ are independently H, halo, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, Selected from cycloalkyl, C _1-6 haloalkyl, CN and NO ₂ ;
R ⁷ and R ⁸ are independently H, halo, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, CN and NO ₂ Selected from;
Alternatively, R ⁷ and R ⁸ together with the C atom to which they are bonded form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered cycloalkyl or heterocycloalkyl ring, respectively. 1, 2 or 3 independently selected from halo, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, CN and NO ₂ . May be substituted with substituents;
R ⁹ is H, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl;
W, W'and W'do not exist independently or independently C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkinylene, O, S, NR ^h , CO, COO, CONR Selected from ^h , SO, SO ₂ , SONR ^h and NR ^h CONR ⁱ , where each of C _1-6 alkylene, C _2-6 alkenylene and C _2-6 alkinylene is optionally halo, C _1-6 . 1, 2 or 3 independently selected from alkyl, C _1-6 haloalkyl, OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, C _1-6 alkyl amino and C _2-8 dialkyl amino. May be substituted with substituents;
X, X'and X'are not present independently or independently from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkinylene, arylene, cycloalkylene, heteroarylene and heterocycloalkylene. Selected, where each of C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkinylene, arylene, cycloalkylene, heteroarylene and heterocycloalkylene may optionally be halo, CN, NO ₂ , OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkoxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-8 alkoxy alkoxy, cycloalkyl, heterocycloalkyl, C (O) It may be substituted with 1, 2 or 3 substituents independently selected from OR ^j , C (O) NR ^{hR i} , amino, C _1-6 alkylamino and C _2-8 dialkylamino;
Y, Y'and Y'do not exist independently or independently C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkinylene, O, S, NR ^h , CO, COO, CONR Selected from ^h , SO, SO ₂ , SONR ^h and NR ^h CONR ⁱ , where each of C _1-6 alkylene, C _2-6 alkenylene and C _2-6 alkinylene is optionally halo, C _1-6 . 1, 2 or 3 independently selected from alkyl, C _1-6 haloalkyl, OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, C _1-6 alkyl amino and C _2-8 dialkyl amino. May be substituted with substituents;
Z, Z'and Z'are independently H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, halosulfanyl, CN, NO ₂ , N ₃ , ^{A2, SR a2 ,} C (O) R ^b2 , C (O) NR ^c2 R ^d2 , C (O) OR ^a2 , OC (O) R ^b2 , OC (O) NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C (O) R ^b2 , NR ^c2 C (O) NR ^c2 R ^d2 , NR ^c2 C (O) OR ^a2 , C (= NR ⁹ ) NR ^c2 R ^d2 , NR ^c2 C (= NR ^g ) NR ^c2 R ^d2 , P (R ^f2 ) ₂ , P (OR ^e2 ) ₂ , P (O) R ^e2 R ^f2 , P (O) OR ^e2 OR ^f2 , S (O) R ^b2 , S (O) NR ^c2 R ^d2 , S (O) ₂ R ^b2 , NR ^c2 S (O) ₂ R ^b2 , S (O) ₂ NR ^c2 R ^d2 , selected from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 . Alkinyl, C _1-6 haloalkyl, halosulfanyl, CN, NO ₂ , N ₃ , or ^a2 , SR ^a2 , C (O) R ^b2 , C (O) NR ^c2 R ^d2 , C (O) OR ^a2 , OC ( O) R ^b2 , OC (O) NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C (O) R ^b2 , NR ^c2 C (O) NR ^c2 R ^d2 , NR ^c2 C (O) OR ^a2 , C ( = NR ^g ) NR ^c2 R ^d2 , NR ^c2 C (= NR ^g ) NR ^c2 R ^d2 , P (R ^f2 ) ₂ , P (OR ^e2 ) ₂ , P (O) R ^e2 R ^f2 , P (O) OR ^e2 OR ^f2 , S (O) R ^b2 , S (O) NR ^c2 R ^d2 , S (O) ₂ R ^b2 , NR ^c2 S (O) ₂ R ^b2 and S (O) ₂ NR ^c2 R ^d2 May be substituted with the selected 1, 2, 3, 4 or 5 substituents;
Here, the two adjacent −WX—Y—Z together with the atom to which they are bonded, optionally fused 4- to 20-membered cycloalkyl ring or condensed 4- to 20-membered heterocycloalkyl ring. May form halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, halosulfanyl, CN, NO ₂ , or ^a3 , SR ^a3 , C, respectively. (O) R ^b3 , C (O) NR ^c3 R ^d3 , C (O) OR ^a3 , OC (O) R ^b3 , OC (O) NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C (O) R ^b3 , NR ^c3 C (O) NR ^c3 R ^d3 , NR ^c3 C (O) OR ^a3 , C (= NR ^g ) NR ^c3 R ^d3 , NR ^c3 C (= NR ^g ) NR ^c3 R ^d3 , S (O) R ^b3 , S (O) NR ^c3 R ^d3 , S (O) ₂ R ^b3 , NR ^c3 S (O) ₂ R ^b3 , S (O) ₂ NR ^c3 R ^d3 , aryl, cycloalkyl, heteroaryl and heterocyclo May be substituted with 1, 2 or 3 substituents selected independently of alkyl;
Here, the two adjacent -W'-X'-Y'-Z' are integrated with the atom to which they are bonded, and in some cases, a condensed 4- to 20-membered cycloalkyl ring or a condensed 4 to 20. A member heterocycloalkyl ring may be formed, optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, halosulfanyl, CN, NO ₂ or, respectively. ^a3 , SR ^a3 , C (O) R ^b3 , C (O) NR ^c3 R ^d3 , C (O) OR ^a3 , OC (O) R ^b3 , OC (O) NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C (O) R ^b3 , NR ^c3 C (O) NR ^c3 R ^d3 , NR ^c3 C (O) OR ^a3 , C (= NR ^g ) NR ^c3 R ^d3 , NR ^c3 C (= NR ^g ) NR ^c3 R ^d3 , S (O) R ^b3 , S (O) NR ^c3 R ^d3 , S (O) ₂ R ^{b3'NR c3} S (O) ₂ R _b3 ^, S (O) ₂ NR ^c3 R ^d3 , aryl, cycloalkyl , May be substituted with 1, 2 or 3 substituents independently selected from heteroaryl and heterocycloalkyl;
Cy ⁴ and Cy ⁵ are independently selected from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C. _1-6 Haloalkyl, halosulfanyl, CN, NO ₂ , N ₃ , or ^a4 , SR ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 , C (O) OR ^a4 , OC (O) R ^b4 , OC (O) NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 C (O) R ^b4 , NR ^c4 C (O) NR ^c4 R ^d4 , NR ^c4 C (O) OR ^a4 , C (= NR ^g ) ) NR ^c4 R ^d4 , NR ^c4 C (= NR ^g ) NR ^c4 R ^d4 , P (R ^f4 ) ₂ , P (OR ⁴ ) ₂ , P (O) R ^e4 R ^f4 , P (O) OR ^e4 OR ^f4 , S (O) ^b4 S (O) NR ^c4 R ^d4 , S (O) ₂ R ^b4 , NR ^c4 S (O) ₂ R ^b4 and S (O) ₂ NR ^c4 R ^d4 independently selected 1 May be substituted with 2, 3, 4 or 5 substituents;
^RA is H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the C _1-4 alkyl, C _{2- 4} Alkenyl, C _2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally selected 1, 2 or 3 substitutions independently of OH, CN, amino, halo and C _1-4 alkyl. May be substituted with a group;
RB is H, ^C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the C _1-4 alkyl, C _{2- 4} Alkenyl or C _2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally selected 1, 2 or 3 substitutions independently of OH, CN, amino, halo and C _1-4 alkyl. May be substituted with a group;
^RC and R ^D are independently selected from H, C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl, where the C _1-4 alkyl, C _2-4 alkenyl or C. _2-4 alkynyls may optionally be substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, halo and C _1-4 alkyl;
Alternatively, ^RC and R ^D together with the N atom to which they are bonded form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl or heteroaryl group, each optionally OH. , CN, amino, halo and may be substituted with 1, 2 or 3 substituents independently selected from C _1-4 alkyl;
R ^a , R ^a1 , R ^a2 , R ^a3 and R ^a4 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkoxy, C _2-6 alkynyl, aryl, cycloalkyl, Selected from heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkoxy, _{C 2 -6} Alkinyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C. May be substituted with 1, 2 or 3 substituents independently selected from _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy;
R ^b , R ^b1 , R ^b2 , R ^b3 and R ^b4 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, Selected from heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkoxy, C _{2 -6} Alkinyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C. May be substituted with 1, 2 or 3 substituents independently selected from _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy;
R ^c and R ^d are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl. , Heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 . May be substituted with 1, 2 or 3 substituents independently selected from haloalkyl and C _1-6 haloalkyl;
Alternatively, R ^c and R ^d together with the N atom to which they are bonded form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl or heteroaryl group, each optionally OH. , CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy substituted with 1, 2 or 3 substituents independently selected. Often;
R ^c1 and R ^d1 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkoxy, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl. , Heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 . May be substituted with 1, 2 or 3 substituents independently selected from haloalkyl and C _1-6 haloalkoxy;
Alternatively, R ^c1 and R ^d1 together with the N atom to which they are attached form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl or heteroaryl group, each optionally OH. , CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy substituted with 1, 2 or 3 substituents independently selected. Often;
R ^c2 and R ^d2 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl. , Heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl and biheteroaryl. , Here, the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl. Alkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl and biheteroaryl are optionally OH, CN, respectively. Amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C (O) OR ^a4 , C (O) ) R ^b4 , S (O) ₂ R ^b3 , alkoxyalkyl and may be substituted with 1, 2 or 3 substituents independently selected from alkoxyalkoxy;
Alternatively, R ^c2 and R ^d2 together with the N atom to which they are attached form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl or heteroaryl group, each optionally OH. , CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C (O) OR ^a4 , It may be substituted with a 1, 2 or 3 substituent independently selected from C (O) R ^b4 , S (O) ₂ R ^b3 , alkoxyalkyl and alkoxyalkoxy;
R ^c3 and R ^d3 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkoxy, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl. , Heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 . May be substituted with 1, 2 or 3 substituents independently selected from haloalkyl and C _1-6 haloalkoxy;
Alternatively, R ^c3 and R ^d3 together with the N atom to which they are attached form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl or heteroaryl group, each optionally OH. , CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy substituted with 1, 2 or 3 substituents independently selected. Often;
R ^c4 and R ^d4 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkoxy, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl. , Heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may be OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 . May be substituted with 1, 2 or 3 substituents independently selected from haloalkyl and C _1-6 haloalkoxy;
Alternatively, R ^c4 and R ^d4 together with the N atom to which they are attached form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl or heteroaryl group, each optionally OH. , CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy substituted with 1, 2 or 3 substituents independently selected. Often;
R ^e , R ^e1 , R ^e2 and R ^e4 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkoxy, (C _1-6 alkoxy) -C _1-6 alkyl, Selected from C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl;
R ^f , R ^f1 , R ^f2 and R ^f4 independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl and Selected from heterocycloalkyl;
R ^g is H, CN and NO ₂ ;
R ^h and R ⁱ are independently selected from H and C _1-6 alkyl;
^Rj is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl. Alkyl or heterocycloalkylalkyl;
m is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, 3 or 4;
q is 0, 1, 2, 3 or 4;
r is 0, 1, 2, 3, 4, 5 or 6;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2, 3 or 4;
However, if A is CH, then L1 is other than CO or (CR ⁴ R ⁵ ) _u (where u is 1). ]
Or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, L ¹ is (CR ⁴ R ⁵ ) _m , where R ⁴ and R ⁵ are independently H and m is 1; Cy ¹ is heteroaryl; R ¹ Is H; A is N; R ² is H; L ² is (CR ⁷ R ⁸ ) _r , where r is 0; Cy ² is 2W'-X'-Y. It is an aryl substituted with'-Z'.

In some embodiments, the INC280 has the following structure:

In some embodiments, INC280 is a 2-fluoro-N-methyl-4- [7- (quinoline-6-ylmethyl) imidazole [1,2-b] [1,2,4] triazine-2-yl] benzamide or It is the pharmaceutically acceptable salt.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with an Alk inhibitor to use a cancer, eg, a cancer described herein (eg, Table 1). Disclosed in the treatment of cancer). In some embodiments, the Alk inhibitor is a publication cited in Table 1 (eg, LDK378) or Table 1, eg, WO2008 / 073687 (eg, Example 7 / Compound 66) or US8,039,479 (eg, eg). , Claim 1 or 5) (disclosed in ceritinib (also known as Dicadia®). In certain embodiments, Alk inhibitors, such as LDK378, are provided in Table 1 or cited in Table 1. It has a structure (compound or general structure) as disclosed in, for example, WO2008 / 073687 (eg, Example 7 / Compound 66) or US8,039,479 (eg, claim 1 or 5). ..

In certain embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with LDK378 for the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treat lymphomas (eg, undifferentiated large cell lymphoma or non-Hodgkin's lymphoma), inflammatory myofibroblastic tumor (IMT) or neuroblastoma. In some embodiments, NSCLC is stage IIIB or IVNSCLC or relapsed locally advanced or metastatic NSCLC. In some embodiments, the cancer (eg, lung cancer, lymphoma, inflammatory myofibroblast tumor or neuroblastoma) is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion. In some embodiments, the ALK fusion is an EML4-ALK fusion, eg, an EML4-ALK fusion described herein. In another embodiment, the ALK fusion is an ALK-ROS1 fusion. In some embodiments, the cancer is advanced or resistant or resistant to a ROS1 or ALK inhibitor, eg, an ALK inhibitor other than LDK378. In some embodiments, the cancer is advanced or resistant or resistant to crizotinib. In some embodiments, the subject is an ALK untreated patient, eg, a human patient. In another embodiment, the subject is a patient, eg, a human patient, who has been pretreated with an ALK inhibitor. In another embodiment, the subject is a patient pretreated with LDK378, eg, a human patient.

In some embodiments, LDK378 and nivolumab are administered to ALK untreated patients. In another embodiment, LDK378 and nivolumab are administered to a patient pretreated with an ALK inhibitor. In yet another embodiment, LDK378 and nivolumab are administered to a patient pretreated with LDK378.

In some embodiments, LDK378 is administered at an oral dose of about 100-1000 mg, such as about 150 mg-900 mg, about 200 mg-800 mg, about 300 mg-700 mg or about 400 mg-600 mg, such as about 150 mg, 300 mg, 450 mg, 600 mg or 750 mg. Administer. In certain embodiments, LDK378 is administered at an oral dose of about 750 mg or less, eg, about 600 mg or less, eg, about 450 mg or less. In some embodiments, LDK378 is administered with a diet. In another embodiment, the administration is hungry. The dosing schedule may change, for example, every other day to every day, twice or three times a day. In certain embodiments, LDK378 is administered daily. In some embodiments, LDK378 is administered at a daily oral dose of about 150 mg to 750 mg with food or on an empty stomach. In some embodiments, LDK378 is administered at an oral dose of 750 mg daily on an empty stomach. In some embodiments, LDK378 is administered in capsules or tablets at a daily oral dose of 750 mg. In another embodiment, LDK378 is administered in capsules or tablets at an oral dose of about 600 mg daily. In some embodiments, LDK378 is administered in capsules or tablets at an oral dose of about 450 mg daily.

In some embodiments, LDK378 is administered at a dose of about 450 mg and nivolumab is administered at a dose of about 3 mg / kg. In another embodiment, the LDK 378 dose is 600 mg and the nivolumab dose is 3 mg / kg. In some embodiments, LDK378 is administered with a low-fat diet.

〔式中、
Ｒ^１はハロまたはＣ_１－６アルキルであり；
Ｒ^２はＨであり；
Ｒ^３は(ＣＲ_２)_０－２ＳＯ_２Ｒ^１２であり；
Ｒ^４はＣ_１－６アルキル、Ｃ_２－６アルケニルまたはＣ_２－６アルキニル；ＯＲ^１２、ＮＲ(Ｒ^１２)、ハロ、ニトロ、ＳＯ_２Ｒ^１２、(ＣＲ_２)_ｐＲ^１３またはＸであるか；またはＲ^４はＨであり；
Ｒ^６はイソプロポキシまたはメトキシであり；
Ｒ^８およびＲ^９の一方は(ＣＲ_２)_ｑＹであり、他方はＣ_１－６アルキル、シアノ、Ｃ(Ｏ)Ｏ_０－１Ｒ^１２、ＣＯＮＲ(Ｒ^１２)またはＣＯＮＲ(ＣＲ_２)_ｐＮＲ(Ｒ^１２)であり；
Ｘは(ＣＲ_２)_ｑＹ、シアノ、Ｃ(Ｏ)Ｏ_０－１Ｒ^１２、ＣＯＮＲ(Ｒ^１２)、ＣＯＮＲ(ＣＲ_２)_ｐＮＲ(Ｒ^１２)、ＣＯＮＲ(ＣＲ_２)_ｐＯＲ^１２、ＣＯＮＲ(ＣＲ_２)_ｐＳＲ^１２、ＣＯＮＲ(ＣＲ_２)_ｐＳ(Ｏ)_１－２Ｒ^１２または(ＣＲ_２)_１－６ＮＲ(ＣＲ_２)_ｐＯＲ^１２であり；
Ｙはピロリジニル、ピペリジニルまたはアゼチジニルであり、その各々フェニル環に炭素原子を介して結合しており；
Ｒ^１２およびＲ^１３は、独立して３～７員飽和または部分的不飽和炭素環式環またはＮ、Ｏおよび／またはＳを含む５～７員ヘテロ環式環；アリールまたはヘテロアリールであるか；またはＲ^１２はＨまたはＣ_１－６アルキルであり；
ＲはＨまたはＣ_１－６アルキルであり；
ｎは０～１であり；
ｐは０～４であり；
ｑは０である。〕
を有するかまたはその薬学的に許容される塩である。 In some embodiments, the Alk inhibitor has the following structure:

[In the ceremony,
R ¹ is halo or C _1-6 alkyl;
R ² is H;
R ³ is (CR ₂ ) _0-2 SO ₂ R ¹² ;
R ⁴ is C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl; OR ¹² , NR (R ¹² ), halo, nitro, SO ₂ R ¹² , (CR ₂ ) _p R ¹³ or X. Or; or ^R4 is H;
^R6 is isopropoxy or methoxy;
One of R ⁸ and R ⁹ is (CR ₂ ) _q Y and the other is C _1-6 alkyl, cyano, C (O) O _0-1 R ¹² , CONR (R ¹² ) or CONR (CR ₂ ) _p . NR (R ¹² );
X is (CR ₂ ) _q Y, cyano, C (O) O _0-1 R ¹² , CONR (R ¹² ), CONR (CR ₂ ) _p NR (R ¹² ), CONR (CR ₂ ) _p OR ¹² , CONR (CR ₂ ) _p SR ¹² , CONR (CR ₂ ) _p S (O) _1-2 R ¹² or (CR ₂ ) _1-6 NR (CR ₂ ) _p OR ¹² ;
Y is pyrrolidinyl, piperidinyl or azetidinyl, each of which is attached to the phenyl ring via a carbon atom;
R ¹² and R ¹³ are independently 3- to 7-membered saturated or partially unsaturated carbocyclic rings or 5- to 7-membered heterocyclic rings containing N, O and / or S; aryl or heteroaryl. Or R ¹² is an H or C _1-6 alkyl;
R is H or C _1-6 alkyl;
n is 0 to 1;
p is 0-4;
q is 0. ]
Or a pharmaceutically acceptable salt thereof.

In some embodiments, R ² is H; R ³ is SO ₂ R ¹² ; R ¹² is C _1-6 alkyl; R ⁴ is H (n = 1); R ⁶ is isopropoxy. Yes; and one of R ⁸ and R ⁹ is (CR ² ) qY, where q = 0, where Y is piperidinyl and the other is C _1-6 alkyl.

In some embodiments, the LDK 378 has the following structure:

In some embodiments, LDK378 comprises 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl) -phenyl) -N4- [2- (propane-2-sulfonyl) -phenyl. ] -Pyrimidine-2,4-diamine or a pharmaceutically acceptable salt thereof.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a CDK4 / 6 inhibitor to use a cancer, eg, a cancer described herein (eg, eg). The cancers disclosed in Table 1) are treated. In some embodiments, the CDK4 / 6 inhibitor is a publication of Table 1 (eg, LEE011) or the publications cited in Table 1, eg, US8,685,980 or US8,415,355 (eg, columns 3-4). It is disclosed in the formula (I) or Example 74) of the column 66. In some embodiments, the CDK4 / 6 inhibitor, eg, LEE011, is a publication provided in Table 1 or cited in Table 1, eg, US8,685,980 or US8,415,355 (eg, Columns 3– It has a structure (compound or general structure) as disclosed in formula (I) of 4 or Example 74) of column 66. In certain embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with LEE011 to include the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treat neurogenic cancer, melanoma or breast cancer or hematopoietic tumors, such as lymphoma.

〔式中、
ＸはＣＲ^９またはＮであり；
Ｒ^１はＣ_１－８アルキル、ＣＮ、Ｃ(Ｏ)ＯＲ^４またはＣＯＮＲ^５Ｒ^６、５～１４員ヘテロアリール基または３～１４員シクロヘテロアルキル基であり；
Ｒ^２はＣ_１－８アルキル、Ｃ_３－１４シクロアルキルまたは５～１４員ヘテロアリール基であり、ここで、Ｒ^２は１以上のＣ_１－８アルキルまたはＯＨで置換されていてよく；
Ｌは結合、Ｃ_１－８アルキレン、Ｃ(Ｏ)またはＣ(Ｏ)ＮＲ^１０であり、ここで、Ｌは置換されていてもされていなくてもよく；
ＹはＨ、Ｒ^１１、ＮＲ^１２Ｒ^１３、ＯＨであるかまたはＹは次の基

の一部であり、ここで、ＹはＣＲ^９またはＮであり；ここで、０～３Ｒ^８が存在してよく、Ｒ^８はＣ_１－８アルキル、オキソ、ハロゲンまたはであるか２以上のＲ^８は架橋アルキル基を形成してよく；
ＷはＣＲ^９またはＮまたはＯであり(ＷがＯであるとき、Ｒ^３は存在しない)；
Ｒ^３は、Ｈ、Ｃ_１－８アルキル、Ｃ_１－８アルキルＲ^１４、Ｃ_３－１４シクロアルキル、Ｃ(Ｏ)Ｃ_１－８アルキル、Ｃ_１－８ハロアルキル、Ｃ_１－８アルキルＯＨ、Ｃ(Ｏ)ＮＲ^１４Ｒ^１５、Ｃ_１－８シアノアルキル、Ｃ(Ｏ)Ｒ^１４、Ｃ_０－８アルキルＣ(Ｏ)Ｃ_０－８アルキルＮＲ^１４Ｒ^１５、Ｃ_０－８アルキルＣ(Ｏ)ＯＲ^１４、ＮＲ^１４Ｒ^１５、ＳＯ_２Ｃ_１－８アルキル、Ｃ_１－８アルキルＣ_３－１４シクロアルキル、Ｃ(Ｏ)Ｃ_１－８アルキルＣ_３－１４シクロアルキル、Ｃ_１－８アルコキシまたはＯＨであり、Ｒ^３がＨ以外であるとき、置換されていてもまたはされていなくてもよく；
Ｒ^９はＨまたはハロゲンであり；
Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４およびＲ^１５は各々独立してＨ、Ｃ_１－８アルキル、Ｃ_３－１４シクロアルキル、３～１４員シクロヘテロアルキル基、Ｃ_６－１４アリール基、５～１４員ヘテロアリール基、アルコキシ、Ｃ(Ｏ)Ｈ、Ｃ(Ｎ)ＯＨ、Ｃ(Ｎ)ＯＣＨ_３、Ｃ(Ｏ)Ｃ_１－３アルキル、Ｃ_１－８アルキルＮＨ_２、Ｃ_１－６アルキルＯＨから選択され、ここで、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３、Ｒ^１４およびＲ^１５は、Ｈ以外であるとき、置換されていてもされていなくてもよく；
ｍおよびｎは、独立して０～２であり；
ここで、Ｌ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３、Ｒ^１４およびＲ^１５は、Ｃ_１－８アルキル、Ｃ_２－８アルケニル、Ｃ_２－８アルキニル、Ｃ_３－１４シクロアルキル、５～１４員ヘテロアリール基、Ｃ_６－１４アリール基、３～１４員シクロヘテロアルキル基、ＯＨ、(Ｏ)、ＣＮ、アルコキシ、ハロゲンまたはＮＨ_２の１以上で置換されていてよい。〕。 In some embodiments, the CDK4 / 6 inhibitor has the following structure:

[In the ceremony,
X is CR ⁹ or N;
R ¹ is a C _1-8 alkyl, CN, C (O) OR ⁴ or CONR ⁵ R ⁶ , 5-14 membered heteroaryl group or 3-14 membered cycloheteroalkyl group;
R ² is a C _1-8 alkyl, C _3-14 cycloalkyl or 5-14 membered heteroaryl group, where R ² may be substituted with one or more C _1-8 alkyl or OH;
L is bound, C _1-8 alkylene, C (O) or C (O) NR ¹⁰ , where L may or may not be substituted;
Y is H, R ¹¹ , NR ¹² R ¹³ , OH or Y is the next group

Where Y is CR ⁹ or N; where 0-3R ⁸ may be present, where R ⁸ is C _1-8 alkyl, oxo, halogen or or more than two. ^R8 may form a crosslinked alkyl group;
W is CR ⁹ or N or O (when W is O, R ³ does not exist);
R ³ is H, C _1-8 alkyl, C _1-8 alkyl R ¹⁴ , C _3-14 cycloalkyl, C (O) C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkyl OH, C (O) NR ¹⁴ R ¹⁵ , C _1-8 Cyanoalkyl, C (O) R ¹⁴ , C _{0-8 Alkoxy} C (O) C _{0-8 Alkoxy} NR ¹⁴ R ¹⁵ , C _{0-8 Alkoxy} C (O) ) OR ¹⁴ , NR ¹⁴ R ¹⁵ , SO ₂ C _1-8 alkyl, C _1-8 alkyl C _3-14 cycloalkyl, C (O) C _1-8 alkyl C _3-14 cycloalkyl, C _1-8 alkoxy Or OH and may or may not be substituted when R ³ is other than H;
R ⁹ is H or halogen;
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently H, C _1-8 alkyl, C _3-14 cycloalkyl, 3 respectively. ~ 14-membered cycloheteroalkyl group, C _6-14 aryl group, 5-14-membered heteroaryl group, alkoxy, C (O) H, C (N) OH, C (N) OCH ₃ , C (O) C ₁ Selected from _-3 alkyl, C _1-8 alkyl NH ₂ , C _1-6 alkyl OH, where R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ , R. ¹⁴ and R ¹⁵ may or may not be substituted when they are other than H;
m and n are 0-2 independently;
Here, L, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ , R ¹⁴ and R ¹⁵ are C _1-8 alkyl, C _2-8 alkoxy. , C _2-8 alkynyl, C _3-14 cycloalkyl, 5-14 membered heteroaryl group, C _6-14 aryl group, 3-14 member cycloheteroalkyl group, OH, (O), CN, alkoxy, halogen or It may be substituted with 1 or more of NH ₂ . ].

の一部であり、ここで、ＹはＮであり、０のＲ^８が存在し、ＷはＮ、ｍおよびｎは両者とも１であり、Ｒ^３はＨである。 In some embodiments, X is CR ⁹ , where R ⁹ is H; R ¹ is CONR ⁵ R ⁶ , where R ⁵ and R ⁶ are both C _1-8 alkyl, specifically. Methyl to; R ² is C _3-14 cycloalkyl, specifically cyclopentyl; L is a bond; Y is a group

Where Y is N, R ⁸ of 0 is present, W is N, m and n are both 1, and R ³ is H.

In some embodiments, the LEE011 has the following structure:

In some embodiments, LEE011 is 7-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-carboxylic acid dimethylamide or a pharmaceutical agent thereof. It is an acceptable salt.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a PI3K inhibitor to use a cancer, eg, a cancer described herein (eg, Table 1). Disclosed in the treatment of cancer). In some embodiments, the PI3K inhibitor is a publication cited in Table 1 (eg, BKM120 or BYL719) or Table 1, eg, WO2007 / 084786 (eg, [0389], Example 10 or formula (0048)). I)) or WO2010 / 029082 (eg, Example 15 or formula (I)). In some embodiments, the PI3K inhibitor, eg, BKM120 or BYL719, is from a publication provided in Table 1 or cited in Table 1, eg, WO2007 / 084786 (eg, Example 10 or [0048] of [0389]. It has a structure (compound or general structure) as disclosed in formula (I)) or WO2010 / 029082 (eg, Example 15 or formula (I)). In some embodiments, one of nibolumab, penbrolizumab or MSB0010718C is used in combination with BKM120 or BYL719 for the cancers or disorders listed in Table 1, eg, solid tumors, eg, lung cancer (eg, non-small cell lung cancer (eg, non-small cell lung cancer). NSCLC))), prostate cancer, endocrine cancer, ovarian cancer, melanoma, bladder cancer, female reproductive system cancer, digestive / gastrointestinal cancer, colon-rectal cancer, polymorphic glioblastoma (GBM), head and neck cancer, gastric cancer, Treat pancreatic cancer or cancer; or hematopoietic tumors, such as leukemia, non-Hodgkin's lymphoma; or impaired hematopoietic development.

〔式中、
ＷはＣＲＷまたはＮであり、ここで、Ｒｗは、(１)水素、(２)シアノ、(３)ハロゲン、(４)メチル、(５)トリフルオロメチルおよび(６)スルホンアミドからなる群から選択され；Ｒ_１は、(１)水素、(２)シアノ、(３)ニトロ、(４)ハロゲン、(５)置換および非置換アルキル、(６)置換および非置換アルケニル、(７)置換および非置換アルキニル、(８)置換および非置換アリール、(９)置換および非置換ヘテロアリール、(１０)置換および非置換ヘテロシクリル、(１１)置換および非置換シクロアルキル、(１２)－ＣＯＲ_１ａ、(１３)－ＣＯ_２Ｒ_１ａ(１４)－ＣＯＮＲ_１ａＲ_１ｂ、(１５)－ＮＲ_１ａＲ_１ｂ、(１６)－ＮＲ_１ａＣＯＲ_１ｂ、(１７)－ＮＲ_１ａＳＯ_２Ｒ_１ｂ、(１８)－ＯＣＯＲ_１ａ、(１９)－ＯＲ_１ａ、(２０)－ＳＲ_１ａ(２１)－ＳＯＲ_１ａ、(２２)－ＳＯ_２Ｒ_１ａおよび(２３)－ＳＯ_２ＮＲ_１ａＲ_１ｂからなる群から選択され、ここで、Ｒ_１ａおよびＲ_１ｂは、独立して(ａ)水素、(ｂ)置換または非置換アルキル、(ｃ)置換および非置換アリール、(ｄ)置換および非置換ヘテロアリール、(ｅ)置換および非置換ヘテロシクリルおよび(ｆ)置換および非置換シクロアルキルからなる群から選択され；Ｒは、(１)水素、(２)シアノ、(３)ニトロ、(４)ハロゲン、(５)ヒドロキシ、(６)アミノ、(７)置換および非置換アルキル、(８)－ＣＯＲ２ａからなる群から選択され、ここで、Ｒ_２ａ－およびＲ_２ｂは、独立して(ａ)水素および(ｂ)置換または非置換アルキルからなる群から選択され；Ｒ_３は、(１)水素、(２)シアノ、(３)ニトロ、(４)ハロゲン、(５)置換および非置換アルキル、(６)置換および非置換アルケニル、(７)置換および非置換アルキニル、(８)置換および非置換アリール、(９)置換および非置換ヘテロアリール、(１０)置換および非置換ヘテロシクリル、(１１)置換および非置換シクロアルキル、(１２)－ＣＯＲ_３ａ、(１３)－ＮＲ_３ａＲ_３ｂ、(１６)－ＯＲ_３ａ、(１７)－ＳＲ_３ａ、(１８)－ＳＯＲ_３ａ、(１９)－ＳＯ_２Ｒ_３および(２０)－ＳＯ_２ＮＲ_３ａＲ_３ｂからなる群から選択され、ここで、Ｒ_３ａおよびＲ_３ｂは、独立してからなる群から選択され、(ａ)水素、(ｂ)置換または非置換アルキル、(ｃ)置換および非置換アリール、(ｄ)置換および非置換ヘテロアリール、(ｅ)置換および非置換ヘテロシクリルおよび(ｆ)置換および非置換シクロアルキル；およびＲ_４は、(１)水素および(２)ハロゲンからなる群から選択される。〕
を有するかまたはその立体異性体、互変異性体もしくは薬学的に許容される塩である。 In some embodiments, the PI3K inhibitor has the following structure:

[In the ceremony,
W is CRW or N, where Rw consists of the group consisting of (1) hydrogen, (2) cyano, (3) halogen, (4) methyl, (5) trifluoromethyl and (6) sulfonamide. Selected; R ₁ is (1) hydrogen, (2) cyano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted alkenyl, (7) substituted and Unsubstituted alkynyl, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12) -COR _1a , ( 13) -CO ₂ R _1a (14) -CONR _1a R _1b , (15) -NR _1a R _1b , (16) -NR _1a COR _1b , (17) -NR _1a SO ₂ R _1b , (18) -OCOR Selected from the group consisting of _1a , (19) -OR _1a , (20) -SR _1a (21) -SOR _1a , (22) -SO ₂ R _1a and (23) -SO ₂ NR _1a R _1b , where , R _1a and R _1b are independently (a) hydrogen, (b) substituted or unsubstituted alkyl, (c) substituted and unsubstituted aryl, (d) substituted and unsubstituted heteroaryl, (e) substituted and non-substituted. Selected from the group consisting of substituted heterocyclyls and (f) substituted and unsubstituted cycloalkyl; R is (1) hydrogen, (2) cyano, (3) nitro, (4) halogen, (5) hydroxy, (6). Selected from the group consisting of amino, (7) substituted and unsubstituted alkyl, (8) -COR2a, where R _2a- and R _2b are independently (a) hydrogen and (b) substituted or unsubstituted alkyl. Selected from the group consisting of; R ₃ is (1) hydrogen, (2) cyano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted alkenyl, (6) substituted and unsubstituted alkenyl. 7) Substituted and unsubstituted alkynyl, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12)- COR _3a , (13) -NR _3a R _3b , (16) -OR _3a , (17) -SR _3a , (18) -SOR _3a , (19) -SO ₂ R ₃ and (20) -SO ₂ NR _3a Selected from the group consisting of R _3b , where R _3a And R _3b are selected from the independent group consisting of (a) hydrogen, (b) substituted or unsubstituted alkyl, (c) substituted and unsubstituted aryl, (d) substituted and unsubstituted heteroaryl, (e). ) Substituted and unsubstituted heterocyclyls and (f) substituted and unsubstituted cycloalkyl; and _R4 are selected from the group consisting of (1) hydrogen and (2) halogen. ]
Or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, W is CRw, Rw is hydrogen, R ₁ is an unsubstituted heterocyclyl, R ₂ is hydrogen, R ₃ is a substituted alkyl, and R ₄ is hydrogen.

In some embodiments, the BKM 120 has the following structure:

In some embodiments, BKM120 is 4- (trifluoromethyl) -5- (2,6-dimorpholinopyrimidine-4-yl) pyridine-2-amine or a pharmaceutically acceptable salt thereof.

〔式中、
Ａは、

からなる群から選択されるヘテロアリールであり；
Ｒ^１は、次の置換基の１個を表し：(１)非置換または置換、好ましくは置換Ｃ_１－Ｃ_７アルキルであり、ここで、該置換基は、次の基の１以上、好ましくは１～９から独立して選択され：重水素、フルオロまたは１～２の次の基：Ｃ_３－Ｃ_５シクロアルキル；(２)場合により置換されていてよいＣ_３－Ｃ_５シクロアルキルであって、ここで、該置換基は独立して、置換Ｃ_３－Ｃ_５シクロアルキルであり、ここで、該置換基は、独立して１以上、好ましくは１～４の次の基から選択され：重水素、Ｃ_１－Ｃ_４アルキル(好ましくはメチル)、フルオロ、シアノ、アミノカルボニル；(３)場合により置換されていてよいフェニルであって、ここで、該置換基は、独立して次の基の１以上、好ましくは１～２から選択され：重水素、ハロ、シアノ、Ｃ_１－Ｃ_７アルキル、Ｃ_１－Ｃ_７アルキルアミノ、ジ(Ｃ_１－Ｃ_７アルキル)アミノ、Ｃ_１－Ｃ_７アルキルアミノカルボニル、ジ(Ｃ_１－Ｃ_７－アルキル)アミノカルボニル、Ｃ_１－Ｃ_７アルコキシ；(４)場合により一または二置換されていてよいアミン；ここで、該置換基は、独立して、次の基から選択され：重水素、Ｃ_１－Ｃ_７アルキル(これは置換されていないかまたは１以上の重水素、フルオロ、クロロ、ヒドロキシルの置換基から選択される基で置換されている)、フェニルスルホニル(これは置換されていないかまたは１以上、好ましくは１のＣ_１－Ｃ_７アルキル、Ｃ_１－Ｃ_７アルコキシ、ジ(Ｃ_１－Ｃ_７－アルキル)アミノ－Ｃ_１－Ｃ_７－アルコキシで置換されている)；(５)置換スルホニル；ここで、該置換基は次の基から選択され：Ｃ_１－Ｃ_７アルキル(これは置換されていないかまたは重水素、フルオロの群から選択される１以上の置換基で置換されている)、ピロリジノ(これは置換されていないかまたは重水素、ヒドロキシル、オキソの群から選択される１以上の置換基；特に１オキソ)；(６)フルオロ、クロロ；Ｒ２は水素であり；Ｒ３は(１)水素、(２)フルオロ、クロロ、(３)場合により置換されていてよいメチルであり、ここで、該置換基は、独立して１以上、好ましくは１～３の次の基であり：重水素、フルオロ、クロロ、ジメチルアミノ：ただし、(Ｓ)－ピロリジン－１,２－ジカルボン酸２－アミド１－({５－[２－(ｔｅｒｔ－ブチル)－ピリミジン－４－イル]－４－メチル－チアゾール－２－イル}－アミド)を除く。〕
を有するかまたはその塩である。 In some embodiments, the PI3K inhibitor has the following structure:

[In the ceremony,
A is

Heteroaryl selected from the group consisting of;
R ¹ represents one of the following substituents: (1) unsubstituted or substituted, preferably substituted C1 _- C7 alkyl, wherein the substituent is _one or more of the following groups, preferably. Are independently selected from 1-9: dehydrogen, fluoro or the next group 1-2: C ₃ -C ₅ cycloalkyl; (2) optionally substituted with C ₃ -C ₅ cycloalkyl. Here, the substituent is independently substituted C3 _- C5 cycloalkyl, where the substituent is independently selected from one or more, preferably 1 to ₄ next groups. (3) Dehydrogen, C1 _{- C4} alkyl (preferably methyl), fluoro, cyano, aminocarbonyl; (3) optionally substituted phenyl, where the substituents are independent. One or more of the following groups, preferably one or two, preferably selected from: dehydrogen, halo, cyano, C1 _{- C7alkyl} , C1 _{- C7alkylamino} , di (C1 _{- C7alkyl} ) amino, C. ₁ -C ₇ alkyl aminocarbonyl, di (C ₁ -C ₇ -alkyl) amino carbonyl, C ₁ -C ₇ alkoxy; (4) optionally mono- or di-substituted amine; where the substituent is , Independently selected from the following groups: dehydrogen, C1 _- C7 alkyl (which is an unsubstituted group or a group selected from _one or more dehydrovalent, fluoro, chloro, hydroxyl substituents: Substituted), phenylsulfonyl (which is not substituted or is 1 or more, preferably ₁ C1 _{- C7alkyl} , C1 _- C7alkoxy, di (C1 _- C7 _- alkyl) amino- C1 _- C7 _- alkoxy substituted); ( ₅ ) substituted sulfonyl; where the substituent is selected from the following groups: C1 _- C7 alkyl (which is unsubstituted or heavy). Substituent with one or more substituents selected from the group of hydrogen, fluoro), pyrrolidino (which is unsubstituted or substituted with one or more substituents selected from the group of heavy hydrogen, hydroxyl, oxo; in particular. 1oxo); (6) fluoro, chloro; R2 is hydrogen; R3 is (1) hydrogen, (2) fluoro, chloro, (3) optionally substituted methyl, where the substitutions are made. The groups are independently one or more, preferably one to three next groups: dehydrogen, fluoro, chloro, dimethylamino: but (S) -pyrrolidin-1,2-dicarboxylic acid 2-amide. 1- ({5- [2- (tert-butyl) -pyrimidine-4-yl] -4-methyl-thiazole-2-yl} -amide) is excluded. ]
Or its salt.

であり；Ｒ^１は置換Ｃ_１－Ｃ_７アルキルであり、ここで、該置換基は、１以上、好ましくは１～９の重水素、フルオロまたはＣ_３－Ｃ_５シクロアルキルから独立して選択され；Ｒ^２は水素であり、Ｒ^３はメチルである。 In some embodiments, A

R ¹ is a substituted C ₁ -C ₇ alkyl, where the substituent is selected independently of 1 or more, preferably 1-9 deuterium, fluoro or C ₃ -C ₅ cycloalkyl. R ² is hydrogen and R ³ is methyl.

In some embodiments, BYL719 has the following structure:

In some embodiments, BYL719 comprises (S) -pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5- [2- (2,2,2-trifluoro-1,1-dimethyl) 2-(2,2,2-trifluoro-1,1-dimethyl). -Ethyl) -pyridin-4-yl] -thiazole-2-yl} -amide) or a pharmaceutically acceptable salt thereof.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a BRAF inhibitor to use a cancer, eg, a cancer described herein (eg, Table 1). Disclosed in the treatment of cancer). In some embodiments, the BRAF inhibitor is a publication cited in Table 1 (eg, LGX818) or Table 1, eg, WO2011 / 025927 (eg, Formula 6 / Compound 6 or formula (Ia) in [0030]). Or US 8,501,758 (eg, disclosed in Example 5 in column 45). In some embodiments, the BRAF inhibitor, eg, LGX818, has a structure (compound or general structure) as disclosed in the publications provided in Table 1 or cited in Table 1. In certain embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with LGX818 to include the cancers listed in Table 1, eg, solid tumors, eg lung cancer (eg, non-small cell lung cancer (NSCLC)). Treats melanoma, such as advanced melanoma, thyroid cancer, such as papillary thyroid cancer or colorectal cancer. In some embodiments, the cancer is identified as having or having a BRAF mutation (eg, BRAF V600E mutation), BRAF wild type, KRAS wild type or activated KRAS mutation. Cancer can be early, middle or late.

〔式中、Ｙは、ＮおよびＣＲ_６から選択され；Ｒ_２、Ｒ_３、Ｒ_５およびＲ_６は、独立して水素、ハロ、シアノ、Ｃ_１－４アルキル、ハロ－置換Ｃ_１－４アルキル、Ｃ_１－４アルコキシおよびハロ－置換Ｃ_１－４アルコキシから選択され；ただし、Ｒ_５がフルオロであり、Ｒ_１が水素、－Ｘ１Ｒ８ａ、－Ｘ_１Ｃ(Ｏ)ＮＲ_８ａＲ_８ｂ、－ＸＮＲ_８ａＸ_２Ｒ_８ｂ、－Ｘ_１ＮＲ_８ａＣ(Ｏ)Ｘ_２ＯＲ_８ｂおよび－Ｘ_１ＮＲ_８ａＳ(Ｏ)_０－２Ｒ_８ｂから選択されるならば、Ｒ_３およびＲ_６は両者とも水素ではなく；Ｒ_４は、－Ｒ_９および－ＮＲ_１０Ｒ_１１から選択され；ここで、Ｒ_９は、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_３－８ヘテロシクロアルキル、アリールおよびヘテロアリールから選択され；ここで、Ｒ_９の該アリール、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリールは、場合によりハロ、シアノ、Ｃ_１－４アルキル、ハロ－置換Ｃ_１－４アルキル、Ｃ_１－４アルコキシおよびハロ－置換Ｃ_１－４アルコキシから独立して選択される１～３の基で置換されていてよく；Ｒ１０およびＲ１１は、独立して水素およびＲ９から選択され；Ｒ７は、水素、Ｃ_１－４アルキル、Ｃ３－５シクロアルキルおよびＣ３－５ヘテロシクロアルキルから選択され；ここで、Ｒ７の該アルキル、シクロアルキルまたはヘテロシクロアルキルは、場合によりハロ、シアノ、ヒドロキシル、Ｃ_１－４アルキル、ハロ－置換Ｃ_１－４アルキル、Ｃ_１－４アルコキシおよびハロ置換Ｃ_１－４アルコキシから独立して選択される１～３の基で置換されていてよい。〕。 In some embodiments, the BRAF inhibitor has the following structure:

[In the formula, Y is selected from N and CR ₆ ; R ₂ , R ₃ , R ₅ and R ₆ are independently hydrogen, halo, cyano, C _1-4 alkyl, halo-substituted C _1-4 . Selected from alkyl, C _1-4 alkoxy and halo-substituted C _1-4 alkoxy; where R ₅ is fluoro and R ₁ is hydrogen, -X1R8a, _-X1C (O) NR _8a R _8b ,- If selected from XNR _8a X ₂ R _8b , -X ₁ NR _8a C (O) X ₂ OR _8b and -X ₁ NR _8a S (O) _0-2 R _8b , both R ₃ and R ₆ are Not hydrogen; R ₄ is selected from -R ₉ and -NR ₁₀ R ₁₁ ; where R ₉ is C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl. And heteroaryl; where the aryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of _R9 is optionally halo, cyano, C _1-4 alkyl, halo-substituted C _1-4 alkyl, C _1-4 alkoxy and halo-substituted C _1-4 alkoxy may be substituted with 1-3 groups independently selected; R10 and R11 are independently selected from hydrogen and R9; R7 is , Hydrogen, C _1-4 alkyl, C3-5 cycloalkyl and C3-5 heterocycloalkyl; where the alkyl, cycloalkyl or heterocycloalkyl of R7 is optionally halo, cyano, hydroxyl, C. It may be substituted with 1-3 groups independently selected from _1-4 alkyl, halo-substituted C _1-4 alkyl, C _1-4 alkoxy and halo substituted C _1-4 alkoxy. ].

In some embodiments, R ₃ is halo (eg, chloro); R ₄ is R ₉ ; R ₉ is C _1-6 alkyl (eg, methyl) and R ₅ is halo (eg, fluoro). Yes, R ₇ is C _1-4 alkyl (eg, isopropyl); Y is CR ₆ ; R ₆ is H. In some embodiments, the LGX818 has the following structure:

In some embodiments, LGX818 comprises methyl (S)-(1-((4- (3- (5-chloro-2-fluoro-3- (methyl sulfonamide) phenyl) -1-isopropyl-1H-pyrazole-4). -Il) Pyrimidine-2-yl) Amino) Propane-2-yl) Carbamate or a pharmaceutically acceptable salt thereof.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with CAR T cells that target CD19 to form a cancer, eg, a cancer described herein. Treat (eg, the cancers disclosed in Table 1). In some embodiments, the CAR T cells targeting CD19 are Table 1 (eg, CTL019) or publications cited in Table 1, eg, WO2012 / 079000 (eg, SEQ ID NO: 12 (eg, full-length CAR)) or It is disclosed in SEQ ID NO: 14 (eg, CD19 scFv). In some embodiments, CAR T cells targeting CD19, such as CTL019, have a structure (compound or general structure) as disclosed in the publications provided in Table 1 or cited in Table 1. In some embodiments, one of nivolumab, penbrolizumab or MSB0010718C is used in combination with CTL019 to treat the cancers listed in Table 1, such as solid tumors or hematopoietic tumors, such as lymphocytic leukemia or non-Hodgkin's lymphoma. ..

In some embodiments, the CAR T cell targeting CD19 has the USAN name TISAGENLECLEUCEL-T. CTL019 is produced by gene modification of T cells that mediate stable insertion by transduction with a self-inactivating, replication-deficient lentivirus (LV) vector containing the CTL019 transgene under the control of the EF-1alpha promoter. CTL019 is a mixture of transgene positive and negative T cells delivered to a subject based on the percentage of transgene positive T cells.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a MEK inhibitor to use a cancer, eg, a cancer described herein (eg, Table 1). Disclosed in the treatment of cancer). In some embodiments, MEK inhibitors are disclosed in Table 1 (eg, MEK162) or publications cited in Table 1, such as WO2003 / 077914 (eg, Example 18 / Compound 29lll or Formula II). In some embodiments, MEK inhibitors, such as MEK162, are disclosed in publications provided in Table 1 or cited in Table 1, eg, WO2003 / 077914 (eg, Example 18 / Compound 29lll or Formula II). Has such a structure (compound or general structure). In some embodiments, one of nivolumab, pembrolizumab or MSB0010718C is used in combination with MEK162 to treat the cancers listed in Table 1. In other embodiments, the cancers or disorders treated with this combination are melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematopoietic tumor or renal cell carcinoma, multilineage. Select from genetic disorders, gastrointestinal / gastrointestinal cancer, gastric cancer or colorectal cancer; or rheumatoid arthritis. In some embodiments, the cancer is identified as having or having a KRAS mutation.

〔式中、
－－－－は任意の結合であり、ただし、環の１個かつだた一つの窒素は二重結合であり；
Ｒ^１、Ｒ^２、Ｒ^９およびＲ^１０は、独立して水素、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＯＲ^３、－Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＯＲ^３、ＮＲ^４Ｃ(Ｏ)ＯＲ^６、－ＯＣ(Ｏ)Ｒ^３、－ＮＲ^４ＳＯ_２Ｒ^６、－ＳＯ_２ＮＲ^３Ｒ^４、－ＮＲ^４Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(ＮＣＮ)ＮＲ^３Ｒ^４、－ＮＲ^３Ｒ^４およびＣ_１－Ｃ_１０アルキル、Ｃ_１－Ｃ_１０アルケニル、Ｃ_２－Ｃ_１０アルキニル、Ｃ_３－Ｃ_１０シクロアルキル、Ｃ_３－Ｃ_１０シクロアルキルアルキル、－Ｓ(Ｏ)_ｊ(Ｃ_１－Ｃ_６アルキル)、－Ｓ(Ｏ)_ｊ(ＣＲ^４Ｒ^５)_ｍ－アリール、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、－Ｏ(ＣＲ^４Ｒ^５)_ｍ－アリール、－ＮＲ^４(ＣＲ^４Ｒ^５)_ｍ－アリール、－Ｏ(ＣＲ^４Ｒ^５)_ｍ－ヘテロアリール、－ＮＲ^４(ＣＲ^４Ｒ^５)_ｍ－ヘテロアリール、－Ｏ(ＣＲ^４Ｒ^５)_ｍ－ヘテロシクリルおよび－ＮＲ^４(ＣＲ^４Ｒ^５)_ｍ－ヘテロシクリルから選択され、ここで、各アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリル部分は、場合によりオキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＮＲ^４ＳＯ_２Ｒ^６、－ＳＯ_２ＮＲ^３Ｒ^４、－Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＯＲ^３、－ＯＣ(Ｏ)Ｒ^３、－ＮＲ^４Ｃ(Ｏ)ＯＲ^６、－ＮＲ^４Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(ＮＣＮ)ＮＲ^３Ｒ^４、－ＯＲ^３、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～５基で置換されていてよく；
Ｒ^３は、水素、トリフルオロメチルおよびＣ_１－Ｃ_１０アルキル、Ｃ_２－Ｃ_１０アルケニル、Ｃ_２－Ｃ_１０アルキニル、Ｃ_３－Ｃ_１０シクロアルキル、Ｃ_３－Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから選択され、ここで、各アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリル部分は、場合によりオキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＮＲ ＳＯ_２Ｒ、－ＳＯ_２ＮＲＲ^”、－Ｃ(Ｏ)Ｒ、－Ｃ(Ｏ)ＯＲ、－ＯＣ(Ｏ)Ｒ、－ＮＲ^’Ｃ(０)０Ｒ^””、－ＮＲ^’Ｃ(Ｏ)Ｒ^”、－Ｃ(Ｏ)ＮＲＲ^”、－ＳＲ’、－Ｓ(Ｏ)Ｒ””、－ＳＯ_２Ｒ^””、－ＮＲＲ^”、－ＮＲ^’Ｃ(０)ＮＲ”Ｒ^”’、－ＮＲ^’Ｃ(ＮＣＮ)ＮＲ^”Ｒ^’”、－ＯＲ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～５基で置換されていてよく；
Ｒ’、Ｒ”およびＲ’”は、独立して、水素、低級アルキル、低級アルケニル、アリールおよびアリールアルキルから選択され；
Ｒ””は、低級アルキル、低級アルケニル、アリールおよびアリールアルキルから選択され；または
Ｒ’、Ｒ”、Ｒ’”またはＲ””のいずれか２個がそれらが結合している原子と一体となって、４～１０員炭素環式、ヘテロアリールまたはヘテロ環式環を形成でき、その各々は、場合によりハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～３基で置換されていてよく；または
Ｒ^３およびＲ^４は、それらが結合している原子と一体となって、４～１０員炭素環式、ヘテロアリールまたはヘテロ環式環を形成でき、その各々は、場合によりハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＮＲ ＳＯ_２Ｒ^””、－ＳＯ_２ＮＲ^’Ｒ^”、－Ｃ(Ｏ)Ｒ、－Ｃ(Ｏ)ＯＲ、－ＯＣ(Ｏ)Ｒ、－ＮＲ^’Ｃ(０)０Ｒ^””、－ＮＲ Ｃ(Ｏ)Ｒ^”、－Ｃ(Ｏ)ＮＲＲ^”、－ＳＯ_２Ｒ^””、－ＮＲ^’Ｒ^”、－ＮＲ^’Ｃ(Ｏ)ＮＲ^”Ｒ^’”、－ＮＲ^’Ｃ(ＮＣＮ)ＮＲ”Ｒ^’”、－ＯＲ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～３基で置換されていてよく；または
Ｒ^４およびＲ^５は、独立して、水素またはＣ_１－Ｃ_６アルキルであるか；または
Ｒ^４およびＲ^５は、それらが結合している原子と一体となって、４～１０員炭素環式、ヘテロアリールまたはヘテロ環式環を形成し、その各々は、場合によりハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＮＲ ＳＯ_２Ｒ、－ＳＯ_２ＮＲ^’Ｒ^”、－Ｃ(Ｏ)Ｒ^””、－Ｃ(Ｏ)ＯＲ^’、－ＯＣ(Ｏ)Ｒ、－ＮＲ^’Ｃ(０)０Ｒ^””、－ＮＲ^’Ｃ(０)Ｒ^”、－Ｃ(Ｏ)ＮＲ^’Ｒ^”、－ＳＯ_２Ｒ^””、－ＮＲ^’Ｒ^”、－ＮＲ^’Ｃ(Ｏ)ＮＲ^”Ｒ^’”、－ＮＲ^’Ｃ(ＮＣＮ)ＮＲ^”Ｒ^’” _５－ＯＲ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～３基で置換されていてよく；
Ｒ^６は、トリフルオロメチルおよびＣ_１－Ｃ_６アルキル、Ｃ_３－Ｃ_１０シクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキルから選択され、ここで、各アルキル、シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリル部分は、場合によりオキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＮＲ ＳＯ_２Ｒ、－ＳＯ_２ＮＲ^’Ｒ^”、－Ｃ(Ｏ)Ｒ、－Ｃ(Ｏ)ＯＲ、－ＯＣ(Ｏ)Ｒ、－ＮＲ^’Ｃ(０)０Ｒ^””、－ＮＲ^’Ｃ(０)Ｒ^”、－Ｃ(Ｏ)ＮＲＲ^”、－ＳＯ_２Ｒ^””、－ＮＲ^’Ｒ、－ＮＲ^’Ｃ(Ｏ)ＮＲ^”Ｒ”、－ＮＲ^’Ｃ(ＮＣＮ)ＮＲ^”Ｒ^’”、－または、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～５基で置換されていてよく；
Ｒ^７は、水素およびＣ_１－Ｃ_１０アルキル、Ｃ_２－Ｃ_１０アルケニル、Ｃ_２－Ｃ_１０アルキニル、Ｃ_３－Ｃ_１０シクロアルキル、Ｃ_３－Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキルから選択され、ここで、各アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリル部分は、場合によりオキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＮＲ^４ＳＯ_２Ｒ^６、－ＳＯ_２ＮＲ^３Ｒ^４、－Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＯＲ^３、－ＯＣ(Ｏ)Ｒ^３、－ＮＲ^４Ｃ(Ｏ)ＯＲ^６、－ＮＲ^４Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＳＯ_２Ｒ^６、－ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(ＮＣＮ)ＮＲ^３Ｒ^４、－ＯＲ^３、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～５基で置換されていてよく；
Ｗは、ヘテロアリール、ヘテロシクリル、－Ｃ(Ｏ)ＯＲ^３、－Ｃ(Ｏ)ＮＲ^３Ｒ^４、－Ｃ(Ｏ)ＮＲ^４ＯＲ^３、－Ｃ(Ｏ)Ｒ^４ＯＲ^３、－Ｃ(Ｏ)(Ｃ_３－Ｃ_１０シクロアルキル)、－Ｃ(Ｏ)(Ｃ_１－Ｃ_１０アルキル)、－Ｃ(Ｏ)(アリール)、－Ｃ(Ｏ)(ヘテロアリール)および－Ｃ(Ｏ)(ヘテロシクリル)から選択され、その各々は、場合により－ＮＲ^３Ｒ^４、－ＯＲ^３、－Ｒ^２およびＣ_１－Ｃ_１０アルキル、Ｃ_２－Ｃ_１０アルケニルおよびＣ_２－Ｃ_１０アルキニルから独立して選択される１～５基で置換されていてよく、その各々は、場合により－ＮＲ^３Ｒ^４および－ＯＲ^３から独立して選択される１または２基で置換されていてよく；
Ｒ^８は、水素、－ＳＣＦ_３、－Ｃｌ、－Ｂｒ、－Ｆ、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＯＲ^３、－Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＯＲ^３,－ＮＲ^４Ｃ(Ｏ)ＯＲ^６、－ＯＣ(Ｏ)Ｒ^３、－ＮＲ^４ＳＯ_２Ｒ^６、－ＳＯ_２ＮＲ^３Ｒ^４、－ＮＲ^４Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＮＲ^３Ｒ^４,－ＮＲ^５Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^３Ｒ^４およびＣ_１－Ｃ_１０アルキル、Ｃ_２－Ｃ_１０アルケニル、Ｃ_２－Ｃ_１０アルキニル、Ｃ_３－Ｃ_１０シクロアルキル、Ｃ_３－Ｃ_１０シクロアルキルアルキル、－Ｓ(Ｏ)_ｊ(Ｃ_１－Ｃ_６アルキル)、－Ｓ(Ｏ)_ｊ(ＣＲ^４Ｒ^５)_ｍ－アリール、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、－Ｏ(ＣＲ^４Ｒ^５)_ｍ－アリール、－ＮＲ^４(ＣＲ^４Ｒ^５)_ｍ－アリール、－Ｏ(ＣＲ^４Ｒ^５)_ｍ－ヘテロアリール、－ＮＲ^４(ＣＲ^４Ｒ^５)_ｍ－ヘテロアリール、－Ｏ(ＣＲ^４Ｒ^５)_ｍ－ヘテロシクリルおよび－ＮＲ^４(ＣＲ^４Ｒ^５)_ｍ－ヘテロシクリルから選択され、ここで、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリル部分は、場合によりオキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、－ＮＲ^４ＳＯ_２Ｒ^６、－ＳＯ_２ＮＲ^３Ｒ^４、－Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＯＲ^３、－ＯＣ(Ｏ)Ｒ^３、－ＮＲ^４Ｃ(Ｏ)ＯＲ^６、－ＮＲ^４Ｃ(Ｏ)Ｒ^３、－Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(Ｏ)ＮＲ^３Ｒ^４、－ＮＲ^５Ｃ(ＮＣＮ)ＮＲ^３Ｒ^４、－ＯＲ^３、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルから独立して選択される１～５基で置換されていてよく；
ｍは０、１、２、３、４または５であり；
ｊは１または２だえる。〕
を有するものおよびその薬学的に許容される塩、プロドラッグおよび溶媒和物である。 In some embodiments, the MEK inhibitor has the following structure:

[In the ceremony,
--- is an arbitrary bond, except that one nitrogen in the ring is a double bond;
R ¹ , R ² , R ⁹ and R ¹⁰ independently contain hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, -OR ³ , -C (O) R ³ ,- C (O) OR ³ , NR ⁴ C (O) OR ⁶ , -OC (O) R ³ , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ⁵ C (NCN) NR ³ R ⁴ , -NR ³ R ⁴ and C ₁ -C ₁₀ alkyl, C _1- C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl alkyl, -S (O) _j (C ₁ -C ₆ alkyl), -S (O) _j ( CR ⁴ R ⁵ ) _m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O (CR ⁴ R ⁵ ) _m -aryl, -NR ⁴ (CR ⁴ R ⁵ ) _m -aryl , -O (CR ⁴ R ⁵ ) _m -heteroaryl, -NR ⁴ (CR ⁴ R ⁵ ) _m -heteroaryl, -O (CR ⁴ R ⁵ ) _m -heterocyclyl and -NR ⁴ (CR ⁴ R ⁵ ) _m -Selected from heterocyclyls, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are optionally oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide. , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -OC (O) R ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ⁵ C (NCN) NR ³ R ⁴ , -OR ³ , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclyl alkyl may be substituted with 1-5 groups independently selected;
R ³ is hydrogen, trifluoromethyl and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl alkyl, aryl, It is selected from arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is optionally oxo, halogen, cyano, nitro, Trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, -NR SO ₂ R, -SO ₂ NRR ^" , -C (O) R, -C (O) OR, -OC (O) R, ^-NR'C (0) 0R ^"" , -NR'C (O) R ^" , -C (O) NRR ^" , -SR ^' , -S (O) R "", -SO ₂ R ^"" , -NRR ^" ,- NR'C (0) NR "R ^"' , -NR ^' C (NCN) NR ^" R ^{' "} , -OR, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl independently selected May be substituted with 1-5 groups;
R', R "and R'" are independently selected from hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl;
R "" is selected from lower alkyl, lower alkenyl, aryl and arylalkyl; or any two of R', R ", R'" or R "" are integrated with the atom to which they are bonded. Can form 4- to 10-membered carbocyclic, heteroaryl or heterocyclic rings, each of which may optionally be halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl. , Arylalkyl, Heteroarylalkyl, Heterocyclyl and Heterocyclylalkyl, may be substituted with 1 to 3 groups independently selected; or R ³ and R ⁴ are integrated with the atom to which they are attached. A 4- to 10-membered carbocyclic, heteroaryl or heterocyclic ring can be formed, each of which may optionally be halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, -NR SO ₂ R. ^"" , -SO ₂ NR'R ^" , -C (O) R, -C (O) OR, -OC (O) R, -NR ^' C (0) 0R ^{" "} , -NR C (O) R ^" , -C (O) NRR ^" , -SO ₂ R ^"" , ^{-NR'R "} , -NR ^' C (O) NR ^" R ^'" , -NR ^' C (NCN) NR" R ^'" ,- It may be substituted with 1 to ³ groups independently selected from OR, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; or ^R4 and R5 may be independently hydrogen or Are they C1 _- C ₆ alkyls; or ^R4 and R5 combine with the atoms to which they are attached to form 4- to 10- ^membered carbocyclic, heteroaryl or heterocyclic rings. Each of them may be halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, -NR SO ₂ R, -SO ₂ NR'R ^" , -C (O) R ^{" "} , -C. (O) OR ^' , -OC (O) R, -NR ^' C (0) 0R ^"" , -NR ^' C (0) R ^" , -C (O) NR ^' R ^" , -SO ₂ R ^"" , -NR'R ^" , -NR ^' C (O) NR ^" R ^'" , -NR ^' C (NCN) NR ^" R ^{' "} ₅ -OR, aryl, heteroaryl, arylalkyl, heteroally It may be substituted with 1 to 3 groups independently selected from lualkyl, heterocyclyl and heterocyclylalkyl;
R ⁶ is selected from trifluoromethyl and C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, aryl, aryl alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, cyclo Alkyl, aryl, heteroaryl and heterocyclyl moieties may be oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, -NR SO ₂ R, -SO ₂ NR'R ^" , -C ^. (O) R, -C (O) OR, -OC (O) R, -NR'C (0) 0R ^{"" , -NR' C} (0) R ^" , -C (O) NRR ^" , -SO ₂ R ^"" , -NR'R, -NR ^' C (O) NR ^" R", -NR ^' C (NCN) NR ^" R ^{' "} ,-or aryl, heteroaryl, arylalkyl, heteroarylalkyl, May be substituted with 1-5 groups independently selected from heterocyclyls and heterocyclylalkyls;
R ⁷ is hydrogen and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl alkyl, aryl, aryl alkyl, hetero. Select from aryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is optionally oxo, halogen, cyano, nitro, trifluoromethyl, Difluoromethoxy, Trifluoromethoxy, Azide, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -OC (O) R ³ ,- NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -SO ₂ R ⁶ , -NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ⁵ C (NCN) NR ³ R ⁴ , -OR ³ , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclyl alkyl substituted with 1-5 groups independently selected. Well;
W is heteroaryl, heterocyclyl, -C (O) OR ³ , -C (O) NR ³ R ⁴ , -C (O) NR ⁴ OR ³ , -C (O) R ⁴ OR ³ , -C (O). ) (C ₃ -C ₁₀ cycloalkyl), -C (O) (C ₁ -C ₁₀ alkyl), -C (O) (aryl), -C (O) (heteroaryl) and -C (O) ( Heterocyclyl), each of which is optionally independent of -NR ³ R ⁴ , -OR ³ , -R ² and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl and C ₂ -C ₁₀ alkynyl. It may be substituted with 1 to 5 selected units, each of which may optionally be substituted with 1 or 2 units independently selected from -NR ³ R ⁴ and -OR ³ ;
R ⁸ is hydrogen, -SCF ₃ , -Cl, -Br, -F, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, -OR ³ , -C (O) R ³ , -C. (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -OC (O) R ³ , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ³ R ⁴ and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl alkyl, -S (O) _j (C ₁ -C ₆ alkyl), -S (O) _j (CR ⁴ R ⁵ ) _m -aryl, aryl, aryl Alkyl, Heteroaryl, Heteroarylalkyl, Heterocyclyl, Heterocyclylalkyl, -O (CR ⁴ R ⁵ ) _m -aryl, -NR ⁴ (CR ⁴ R ⁵ ) _m -aryl, -O (CR ⁴ R ⁵ ) _m -Hetero Aryl, -NR ⁴ (CR ⁴ R ⁵ ) _m -heteroaryl, -O (CR ⁴ R ⁵ ) _m -heterocyclyl and -NR ⁴ (CR ⁴ R ⁵ ) _m -heterocyclyl are selected from here, alkyl, alkenyl. , Alkinyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties may be oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR. ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -OC (O) R ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ⁵ C (NCN) NR ³ R ⁴ , -OR ³ , aryl, heteroaryl, arylalkyl, May be substituted with 1-5 groups independently selected from heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
m is 0, 1, 2, 3, 4 or 5;
j is 1 or 2. ]
And pharmaceutically acceptable salts, prodrugs and solvates thereof.

In some embodiments, R ⁷ is C _\ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkyl alkyl, each optionally oxo, halogen, cyano, nitro, trifluoromethyl. , Difluoromethoxy, Trifluoromethoxy, Azide, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -OC (O) R ³ , -SO ₂ R ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ⁵ C (NCN) NR ³ R ⁴ , -OR ³ , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclyl alkyl substituted with 1 to 3 groups independently selected. You may be.

In some embodiments, R ¹ is a halogen; R ² is hydrogen; R ³ is an OR'substituted C ₁ -C ₁₀ alkyl, R'is hydrogen; R ⁴ is hydrogen; R ⁷ is C ₁ -C ₁₀ alkyl; R ⁸ is bromo; R ⁹ is halogen; R ¹⁰ is hydrogen; W is -C (O) NR ⁴ OR ³ .

In some embodiments, MEK162 has the following structure:

In some embodiments, MEK162 comprises 5-((4-bromo-2-fluorophenyl) amino) -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-benzo [d] imidazole-6-. Carboxamide or a pharmaceutically acceptable salt thereof.

In some embodiments, an inhibitor of an immune checkpoint molecule (alone or in combination with other immunomodulators) is used in combination with a BCR-ABL inhibitor to use a cancer, eg, a cancer described herein (eg, eg). The cancers disclosed in Table 1) are treated. In some embodiments, the BCR-ABL inhibitor is a publication cited in Table 1 (eg, AMN-107) or Table 1, eg, WO2004 / 005281 (eg, Formula 92 or claim 1). ) Or US 7,169,791 (eg, claim 8). In some embodiments, AMN-107 is a publication provided in or cited in Table 1, eg, WO2004 / 005281 (eg, Formula 92 in Example 92 or claim 1) or US 7,169,. It has a structure (compound or general structure) as disclosed in 791 (eg, claim 8). In certain embodiments, one of nibolumab, penbrolizumab or MSB0010718C is used in combination with AMN-107 for the cancers or disorders listed in Table 1, such as solid tumors such as neurological cancer, leukemia, digestive organs / Treats gastrointestinal cancer, colorectal cancer, head and neck cancer; or hematopoietic tumors such as chronic myelogenous leukemia (CML), lymphocytic leukemia, myelogenous leukemia; Parkinson's disease; or pulmonary hypertension.

〔式中、
Ｒ_１は水素、低級アルキル、低級アルコキシ－低級アルキル、アシルオキシ－低級アルキル、カルボキシ－低級アルキル、低級アルコキシカルボニル－低級アルキルまたはフェニル－低級アルキルであり；
Ｒ_２は水素、場合により１以上の同一または異なる基で置換されていてよＲ_３低級アルキル、シクロアルキル、ベンズシクロアルキル、ヘテロシクリル、アリール基または０、１、２または３環窒素原子および０または１酸素原子および０または１硫黄原子を含む単環または二環式ヘテロアリール基であり、この基は、各々、非置換であるかまたは一置換もしくは多置換されており；
Ｒ_３はヒドロキシ、低級アルコキシ、アシルオキシ、カルボキシ、低級アルコキシカルボニル、カルバモイル、Ｎ－一置換またはＮ,Ｎ－二置換カルバモイル、アミノ、一または二置換アミノ、シクロアルキル、ヘテロシクリル、アリール基または０、１、２または３環窒素原子および０または１酸素原子および０または１硫黄原子を含む単環または二環式ヘテロアリール基であり、この基は、各々、非置換であるかまたは一置換もしくは多置換されており；または
Ｒ_１およびＲ_２は、一体となって、場合により、低級アルキル、シクロアルキル、ヘテロシクリル、フェニル、ヒドロキシ、低級アルコキシ、アミノ、一または二置換アミノ、オキソ、ピリジル、ピラジニルまたはピリミジニルで一または二置換されていてよい４、５または６炭素原子を有するアルキレン；４または５炭素原子を有するベンズアルキレン；１酸素および３または４炭素原子を有するオキサアルキレン；または１窒素および３または４炭素原子を有するアザアルキレンであり、ここで、窒素は置換されていないかまたは低級アルキル、フェニル－低級アルキル、低級アルコキシカルボニル－低級アルキル、カルボキシ－低級アルキル、カルバモイル－低級アルキル、Ｎ－一置換またはＮ,Ｎ－二置換カルバモイル－低級アルキル、シクロアルキル、低級アルコキシカルボニル、カルボキシ、フェニル、置換フェニル、ピリジニル、ピリミジニルまたはピラジニルで置換されており；
Ｒ_４は水素、低級アルキルまたはハロゲンである。〕
を有するおよびこのような化合物のＮ－オキシドまたは薬学的に許容される塩である。 In some embodiments, the BCR-ABL inhibitor has the following structure:

[In the ceremony,
R ₁ is hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkyl;
R ₂ may be substituted with hydrogen, optionally one or more identical or different groups. R ₃ lower alkyl, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group or 0, 1, 2 or 3 ring nitrogen atom and 0 or A monocyclic or bicyclic heteroaryl group containing 1 oxygen atom and 0 or 1 sulfur atom, each of which is unsubstituted, mono- or poly-substituted;
R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-unisubstituted or N, N-disubstituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyl, heterocyclyl, aryl group or 0,1 A monocyclic or bicyclic heteroaryl group containing a 2, or tricyclic nitrogen atom and a 0 or 1 oxygen atom and a 0 or 1 sulfur atom, each of which is unsubstituted or monosubstituted or polysubstituted, respectively. Or R ₁ and R ₂ together, optionally lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or di-substituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl. An alkylene having 4, 5 or 6 carbon atoms which may be mono or disubstituted with; a benzalkylene having 4 or 5 carbon atoms; an oxaalkylene having 1 oxygen and 3 or 4 carbon atoms; or 1 nitrogen and 3 or 4 Azaalkylenes with carbon atoms, where nitrogen is unsubstituted or lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-monosubstituted or N, N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl substituted;
_R4 is hydrogen, lower alkyl or halogen. ]
And N-oxides of such compounds or pharmaceutically acceptable salts.

で置換されたフェニルであり；Ｒ４はＣＨ_３である。 In some embodiments, R ₁ is hydrogen and R ₂ is CF ₃ and

It is phenyl substituted with; R4 is _CH3 .

In some embodiments, AMN-107 has the following structure:

In some embodiments, AMN-107 comprises 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazole 1-yl)-. 3- (Trifluoromethyl) phenyl] benzamide or N-oxide or a pharmaceutically acceptable salt thereof.

LCL161 and the immunomodulator LCL161, also known as SMAC mimicking LCL161, is a second mitochondrial-derived activator (SMAC) mimetic and IAP (inhibitor of apoptotic protein) of orally bioavailable caspase with anti-neoplastic activity. It is an inhibitor of a family of proteins. The SMAC mimicking LCL161 binds to the X chromosome-related IAP (XIAP) and IAPs such as cellular IAPs 1 and 2. Because IAP shields cancer cells from the process of apoptosis, this agent can be used to restore and promote induction of apoptosis through the apoptotic signaling pathway in cancer cells. IAP suppresses apoptosis by binding to and inhibiting active caspase-3, -7 and -9, which are overexpressed in many cancer cell types and have essential roles in apoptosis (programmed cell death), necrosis and inflammation. do.

In some embodiments, LCL161 is a publication provided in or cited in Table 1, eg, International Patent Publication WO 2008/016893 (eg, Formula (I), Example 1 and Compound A), European Patent No. 2051990. And have a structure as disclosed in US Pat. No. 8,546,336.

In some embodiments, the LCL161 has the following structure:

In some embodiments, the LCL161 comprises (S) -N-((S) -1-cyclohexyl-2-((S) -2-(4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl). )-2-oxoethyl) -2- (methylamino) propanamide.

In some embodiments, immunomodulatory, eg, immune checkpoint molecule inhibitors (eg, PD-1 inhibitors, such as nivolumab or pembrolizumab, PD-L1 inhibitors, such as MSB0010718C or TIM-3 inhibitors, such as, eg. Anti-TIM-3 antibody molecule) in combination with LCL161 to treat cancers or disorders listed in Table 1, such as solid tumors, such as breast cancer or pancreatic cancer; or hematopoietic tumors, such as multiple myeloma or hematopoietic disorders. Used to do.

In some embodiments, an inhibitor of an immune checkpoint molecule (eg, an anti-PD-1 antibody molecule or an anti-TIM-3 antibody molecule) is administered intravenously. In some embodiments, LCL161 is orally administered in combination therapy. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, an anti-PD-1 antibody molecule or an anti-TIM-3 antibody molecule) is administered with LCL161, eg, orally, for at least 1, 2, or 3 days. Administer 4 days, 5 days, 6 days or 7 days, eg, 3 days later, eg, intravenously. In some embodiments, an inhibitor of an immune checkpoint molecule (eg, an anti-PD-1 antibody molecule or an anti-TIM-3 antibody molecule) is administered with LCL161, eg, orally, at least 1 day, 2 days, 3 days. It is administered on the 4th, 5th, 6th or 7th day, for example, on the 3rd day, for example, intravenously. In yet another embodiment, an inhibitor of an immune checkpoint molecule (eg, an anti-PD-1 antibody molecule or an anti-TIM-3 antibody molecule), eg, on the same day that LCL161 is administered orally, eg, Administer intravenously.

In some embodiments, administration of an inhibitor of an immune checkpoint molecule (eg, an anti-PD-1 antibody molecule or an anti-TIM-3 antibody molecule) and LCL161 results in a synergistic effect. In some embodiments, in combination therapy, the concentration of LCL161 required to achieve inhibition, eg, growth inhibition, is lower than the therapeutic dose of monotherapy of LCL161, eg, 10-20%, 20-30%, 30. -40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower. In other embodiments, the concentration of an inhibitor of an immune checkpoint molecule (eg, an anti-PD-1 antibody molecule or an anti-TIM-3 antibody molecule) required to achieve inhibition, eg, growth inhibition, in combination therapy. Lower than the therapeutic dose of monotherapy with an inhibitor of an immune checkpoint molecule (eg, anti-PD-1 antibody molecule or anti-TIM-3 antibody molecule), eg, 10-20%, 20-30%, 30-40% , 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower. In some embodiments, administration of LCL161 alone or in combination with an anti-PD-1 antibody molecule increases the expression of immunoactive cytokines, such as IFN-gamma, in the cancer or subject. In other embodiments, administration of LCL161 alone or in combination with an anti-PD-1 antibody molecule reduces the expression of immunosuppressive cytokines, such as IL-10, in the cancer or subject.

In certain embodiments, the LCL161 is taken from about 10 to 3000 mg, such as about 20 to 2400 mg, about 50 to 1800 mg, about 100 to 1500 mg, about 200 to 1200 mg, about 300 to 900 mg, such as about 600 mg, about 900 mg, about 1200 mg. Administer at doses of about 1500 mg, about 1800 mg, about 2100 mg or about 2400 mg (eg, oral doses). In some embodiments, LCL161 is administered once a week or once every two weeks.

LDK378 and nivolumab LDK378 (Ceritinib) are anaplastic lymphoma kinase (ALK) inhibitors. Its chemical formula is 5-chloro-N ^2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl) phenyl) -N ^4- [2- (propane-2-sulfonyl) -phenyl] -pyrimidine. It is -2,4-diamine. The method for producing LDK378 is disclosed in WO2008 / 073687. The compound has been approved by the USFDA as Zicadia® for the treatment of patients with anaplastic lymphoma kinase (ALK) -positive metastatic non-small cell lung cancer (NSCLC) who are advanced or intolerant to crizotinib. ing. The currently approved daily dose for use of LDK378 (alone) in NSCLC is 750 mg orally when the stomach is empty (ie, should not be administered within 2 hours after a meal).

In clinical trials, LDK378 showed a high rate of rapid and sustained response in 246 ALK-positive NSCLC patients treated with the 750 mg dose group (RD). In these patients, the response rate (ORR) was 58.5%. Of the 144 ALK-positive NSCLC patients with confirmed complete response (CR) or partial response (PR), 86.1% of these patients achieved a response within 12 weeks with a median time to response of 6 It was a week. The estimated central response period (DOR) based on the investigator's evaluation was long at 9.69 months. Central progression-free survival (PFS) was 8.21 months and was discontinued by 53.3% of patients. Importantly, ceritinib exhibits this level of high anti-cancer activity regardless of the previous ALK inhibitor status (ie, whether the patient has been previously treated with an ALK inhibitor). High ORRs of 54.6% and 66.3% were observed in patients treated with previous ALK inhibitors and in patients not treated with ALK inhibitors, respectively.

However, metastatic ALK-positive NSCLC remains a difficult disease to treat. The use of the immune system to treat patients with NSCLC represents a novel and novel treatment approach, and nivolumab can be safely combined with LDK378. Combination therapy including targeting agent LDK378 and immunotherapy (nivolumab) can improve progressionless survival and ultimately overall survival in NSCLC patients.

In one aspect, the invention relates to pharmaceutical combinations, particularly pharmaceutical combination products, comprising combinations of immunomodulators and the agents disclosed herein.

According to the present disclosure, the compound, element (i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) nivolumab or a pharmaceutically acceptable salt thereof in a pharmaceutical combination may be administered separately or together.

According to the present disclosure, the pharmaceutical combination agent used as a pharmaceutical agent may administer LDK378 and nivolumab independently, simultaneously or separately within a certain time interval, and the time intervals referred to herein are jointly administered by these combination partners. The interval that allows it to be active.

The term "pharmaceutical combination" as used herein refers to the active ingredient in a non-fixed combination, eg, (i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) nivolumab or a pharmaceutically acceptable salt thereof. Refers to products obtained by mixing or combining separately or together.

The term "unfixed combination" means that the active ingredients, such as LDK378 and nivolumab, are both administered separately or together, independently, simultaneously or separately within a time interval, such as Administration provides a therapeutically effective concentration of active ingredient in the subject in need of it. The latter is also applied to cocktail therapy, eg administration of 3 or more active ingredients. The term is "kit" in that the combination partners (i) LDK378 and (ii) nivolumab (and one more concomitant drug, if any), as defined herein, can be administered independently of each other.

The term "therapeutically effective in combination" means that these compounds are used separately or together, independently, simultaneously or within a time interval for the treatment of subjects in need of treatment, such as warm-blooded animals, especially humans. Means to show synergistic interactions when administered separately.

The combination of the invention has favorable therapeutic properties such as synergistic interactions, strong in vivo and in vitro antitumor responses, which have been shown to be pharmaceutically usable. This property makes this product particularly useful for the treatment of cancer.

Suitable cancers that can be treated with the combinations of the invention include, but are not limited to, anaplastic large cell lymphoma (ALCL), neuroblastoma, lung cancer, non-small cell lung cancer (NSCLC). In a preferred embodiment, the cancer is NSCLC.

The combinations of the invention may otherwise or in addition be administered in combination with chemotherapy, radiation therapy, immunotherapy, surgical procedures or combinations thereof, especially for the treatment of cancer. Long-term treatment is also possible as an adjuvant treatment in other treatment strategies, as described above. Other possible treatments are, for example, therapeutic or prophylactic chemotherapy to maintain the patient's condition after tumor regression in patients at risk.

The combination of LDK378 and nivolumab can be used in the manufacture of pharmaceuticals for ALK-mediated diseases as described above. Similarly, the combination can be used in the treatment of ALK, which is pharmaceutically acceptable by the present disclosure in an effective amount of (i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) nivolumab or pharmaceutically acceptable thereof. Containing the administration of a combination of salts separately or together to a subject in need of treatment.

For example, the term "combination (therapeutic) activity" refers to these compounds at time intervals that exhibit (preferably synergistic) interactions (preferably synergistic) interactions (preferably synergistic) with warm-blooded animals, especially humans, to be treated. , Can mean that they can be given separately or sequentially (in a staggered manner, especially in an order-specific manner). The therapeutic effect of the combination can be determined, among other things, by tracking blood levels, indicating that both compounds are present in the blood of the treated human for at least some time interval, although the compounds exhibit concomitant activity. At the same time, it does not exclude cases where it is not present in the blood.

The present disclosure also describes a method of treating an ALK-mediated disease in which (i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) nivolumab or a combination of a pharmaceutically acceptable salt thereof are administered separately or together. Is described.

The present disclosure relates to a pharmaceutical composition comprising (i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) an effective amount of nivolumab or a pharmaceutically acceptable salt thereof.

The disclosure also describes pharmaceutical combinations of the invention in the form of "kits" for combined administration. Combination means a fixed combination in one dose unit form or a kit for combined administration, (i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) nivolumab or pharmaceutically acceptable thereof. The salts can be administered independently, simultaneously or separately within a time interval, in particular these time intervals allow the combination partner to exhibit a collaborative (= combination) effect. Parts of an independent formulation or formulation, product or composition can then be administered, eg, simultaneously or temporally staggered, i.e., at different times and for any part of the kit at equal or different time intervals. .. In the combined treatment of the present invention, the compounds useful by the present disclosure may be manufactured and / or formulated by the same or different vendors. In addition, the combination partner may (i) before the combination product is provided to the physician (eg, for kits containing LDK378 and nivolumab); (ii) by the physician himself (or under the guidance of the physician) immediately prior to administration; iii) Patients themselves may be subjected to combination therapy, for example during sequential administration of the disclosed compounds and other therapeutic agents. In some embodiments, the effects of the combination are synergistic.

The therapeutically effective dose of the combination or pharmaceutical composition of the invention can be determined by standard clinical techniques depending on the species, weight, age and individual condition, disorder or disease or severity thereof of the subject. In addition, in vitro or in vivo assays can optionally be used to assist in determining the optimal dose range. The exact dose to be used can be determined by the route of administration and the severity of the condition being treated, eg, with reference to published clinical trials, by the judgment of the practitioner and the circumstances of each subject. In general, satisfactory results have been shown to be obtained systemically with daily doses of 150 mg to 750 mg of LDK378 orally. In most cases, the daily dose of LDK378 can be between 300 mg and 750 mg.

When administered in combination with nivolumab, LDK378 may be administered at 450 mg with 3 mg / kg nivolumab, 600 mg LDK378 with 3 mg / kg nivolumab or 300 mg LDK378 with 3 mg / kg nivolumab. The most preferred doses of both compounds for combination therapy are 600 mg LDK378 and 3 mg / kg nivolumab. In particular, 600 mg LDK378 and 3 mg / kg nivolumab are the most preferred dosing regimens for the treatment of ALK-positive (eg, EML4-ALK) NSCLC. Nivolumab can be administered as a quantitative infusion every two weeks. Ceritinib should be taken with a low-fat diet. Ceritinib is acceptable if administered within 30 minutes of ingesting a low-fat diet. Patients should refrain from eating for at least 1 hour after taking ceritinib and a low-fat diet. Ceritinib administration with daily dietary intake is expected to reduce the incidence and / or severity of gastrointestinal events. Constant exposure to 450 mg and 600 mg of ceritinib with daily low-fat diet intake is model-based using an established pharmacokinetic model of ALK-positive cancer patients combining absorption parameters estimated from one clinical trial and another. It is estimated to be within 20% compared to that achieved with the recommended Phase II dose of 750 mg ceritinib administered on an empty stomach, as predicted by clinical trial simulations.

"Low-fat diet" here means a diet containing about 1.5-15 g of fat and about 100-500 total calories.

Without being bound by theory, ceritinib has no mechanism of action expected to antagonize the immune response. In addition, immune-related adverse events have not been frequently reported in ceritinib trials. Possible overlapping toxicities of ceritinib and nivolumab include diarrhea, nausea, elevated AST and ALT, interstitial pneumonia and hyperglycemia. Given that the mechanisms of action and safety profiles of these toxicities are controlled, the mechanisms of action of these toxicities are not expected to be similar.

Another aspect of the invention is LDK378 for pharmaceutical use, where LDK378 or a pharmaceutically acceptable salt thereof is nivolumab or pharmaceutically acceptable thereof for the treatment of ALK-mediated diseases such as cancer. It is administered in combination with salt.

The term "ALK-mediated disease" refers to abnormalities in the regulatory pathway, including overexpression in cells, mutations or relative deletions in the activity of other regulatory pathways, where kinase activity results in excessive cell proliferation, eg cancer. It is a disease that causes activity. In some embodiments, the ALK-mediated disease can be non-small cell lung cancer (NSCLC) driven by the anaplastic lymphoma kinase (ALK) translocation. ALK is a receptor tyrosine kinase of the insulin receptor superfamily that has a role in nerve development and function. ALK is translocated, mutated and / or amplified in several tumor types, and therefore ALK-mediated diseases include neuroblastoma and anaplastic large cell lymphoma (ALCL) in addition to NSCLC. Modifications in ALK have an important role in the etiology of these tumors. Other ALK fusion partners other than EML4 that may be involved in ALK-mediated disease are KIF5B, TFG, KLC1 and PTPN3, but are expected to be less common than EML4. In preclinical experiments, a variety of ALK fusion partners in vitro and in vivo mediated ligand-independent dimerization / oligomerization of ALK leading to constitutive kinase activity and potent carcinogenic activity, hence m, translocation. When occurs, it indicates that ALK drives, or mediates, the disease.

Further preferred embodiments are described below, either alone or in combination:
1. A pharmaceutical combination comprising (i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) nivolumab or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical combination agent according to Item 1, which comprises the elements (i) and (ii) separately or together.

3. The pharmaceutical combination agent according to Item 1 or 2 for use as a pharmaceutical agent in which LDK378 and nivolumab are administered independently at the same time or separately within a certain time interval.

4. The time interval allows the combination partner to be active in combination, item 3.
The pharmaceutical combination agent described in.

5. The pharmaceutical combination agent according to any one of Items 1 to 4, which comprises an amount that is therapeutically effective in combination for the treatment of ALK-mediated diseases.

6. The pharmaceutical combination agent according to Item 5, wherein the ALK-mediated disease is cancer.

7. The pharmaceutical combination agent according to Item 6, wherein the ALK-mediated disease is NSCLC or lymphoma.

8. The pharmaceutical combination agent according to Item 6, wherein the ALK-mediated disease is NSCLC.

9. The pharmaceutical combination agent according to any one of Items 1 to 8 for use as a pharmaceutical.

10. The pharmaceutical combination agent according to any one of Items 1 to 8 for use in the treatment of cancer.

11. The pharmaceutical combination agent according to Item 10, wherein the cancer is non-small cell lung cancer.

12. Use of LDK378 in combination with nivolumab for the manufacture of drugs for ALK-mediated diseases.

13. Use of LDK378 in combination with nivolumab for the manufacture of the pharmaceuticals according to Item 12, wherein the disease is cancer.

14. Use of LDK378 in combination with nivolumab for the manufacture of the pharmaceutical agent according to Item 13, wherein the cancer is non-small cell lung cancer.

15. A pharmaceutical composition comprising LDK378 or a pharmaceutically acceptable salt thereof and nivolumab or a pharmaceutically acceptable salt thereof for simultaneous or separate administration for the treatment of cancer.

16. The pharmaceutical composition according to Item 15, wherein the cancer is non-small cell lung cancer.

17. The pharmaceutical composition according to Item 22 or 23, wherein the composition comprises an effective amount of LDK378 and nivolumab.

18. The pharmaceutical composition according to any one of Items 15 to 18, further comprising a pharmaceutically acceptable carrier.

19. LDK378 for use as a pharmaceutical, wherein LDK378 or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab or a pharmaceutically acceptable salt thereof.

20. LDK378 for use as the pharmaceutical according to Item 19, for the treatment of cancer.

21. LDK378 for use as the pharmaceutical according to Item 20, wherein the cancer is non-small cell lung cancer.

22. The pharmaceutical combination agent according to any one of Items 1 to 11, in the form of a kit for combined administration.

23. The pharmaceutical combination according to Item 22., wherein LDK378 or a pharmaceutically acceptable salt thereof and nivolumab or a pharmaceutically acceptable salt thereof are administered together or independently at the same time or separately within a certain time interval. ..

24. A method of treating cancer in a subject in need of treatment, wherein a therapeutically effective amount of i) LDK378 or a pharmaceutically acceptable salt thereof and (ii) nivolumab or pharmaceutically acceptable thereof. A method comprising administering salt.

25. A pharmaceutical combination according to any of Items 3-11, 22 or 23, use of LDK378 and nivolumab to an ALK untreated patient, use according to any of Items 12-14, methods of treating cancer according to Item 24, LDK378 for use as a pharmaceutical composition according to any one of Items 15-18 or as a pharmaceutical according to any one of Items 19-21.

26. Pharmaceutical combination according to any of Items 3-11, 22 or 23, use of LDK378 and nivolumab to a patient pretreated with an ALK inhibitor, according to Item 24. A method for treating cancer, LDK378 for use as a pharmaceutical composition according to any of items 15-18 or as a pharmaceutical according to any of items 19-21.

27. LDK378 and nivolumab administered to patients pretreated with LDK378, a pharmaceutical combination according to any of Items 3-11, 22 or 23, use according to any of Items 12-14, cancer according to Item 24. LDK378 for use as a method of treatment, a pharmaceutical composition according to any of items 15-18 or a pharmaceutical according to any of items 19-21.

28. Pharmaceutical combination according to any of Items 3-11, 22, 23 or 25-27, use according to any of Items 12-14 or 25-27, Item 24-27, wherein the cancer comprises an ALK translocation or rearrangement. 27. A method for treating cancer according to any of 27, LDK378 for use as a pharmaceutical composition according to any of Items 15-18 or 25-27 or as a pharmaceutical according to any of Items 19-21 or 25-27.

29. Pharmaceutical combination according to any of Items 3-11, 22, 23 or 25-27, use according to any of Items 12-14 or 25-27, Item 24-27, wherein the cancer comprises an EML4-ALK fusion. A method for treating cancer according to any, LDK378 for use as a pharmaceutical composition according to any of items 15-18 or 25-27 or as a medicine according to any of items 19-21 or 25-27.

30. Pharmaceutical combination according to any of Items 3-11, 22, 23 or 25-27, use according to any of Items 12-14 or 25-27, Item 24-27, wherein the cancer comprises ALK-ROS1 fusion. A method for treating cancer according to any, a pharmaceutical composition according to any of items 15-18 or LDK378 for use as a pharmaceutical according to any of 25-27 or 19-21 or 25-27.

31. Pharmaceutical combination according to any of Items 1-11, 22, 23 or 25-30, wherein the ceritinib dose is 450 mg and the nivolumab dose is 3 mg / kg, according to any of Items 12-14 or 25-30. Use, method for treating cancer according to any of items 24-30, pharmaceutical composition according to any of items 15-18 or 25-30 or for use as a pharmaceutical according to any of items 19-21 or 25-30. LDK378.

32. Pharmaceutical combination according to any of Items 1-11, 22, 23 or 25-30, wherein the ceritinib dose is 600 mg and the nivolumab dose is 3 mg / kg, according to any of Items 12-14 or 25-30. Use, method for treating cancer according to any of items 24-30, pharmaceutical composition according to any of items 15-18 or 25-30 or for use as a pharmaceutical according to any of items 19-21 or 25-30. LDK378.

33. Ceritinib administered with a low-fat diet, pharmaceutical combination according to any of items 1-11, 22, 23 or 25-32, use according to any of items 12-14 or 25-32, items 24-32. A method for treating cancer according to any, LDK378 for use as a pharmaceutical composition according to any of items 15-18 or 25-32 or as a medicine according to any of items 19-21 or 25-32.

EGF816 and nivolumab lung cancer are the most common cancers in the world, and subtype non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer cases. It has been reported that in Western countries 10-15% of NSCLC patients develop epidermal growth factor receptor (EGFR) mutations in their tumors, and in Asian countries the mutation rate is even higher, as high as 40%. ing. L858R and exon 19 deletion (Ex19del) activated EGFR carcinogenic mutations predominate in NSCLC patients, accounting for 38% and 46% of EGFR NSCLC mutations, respectively. EGFR exon 20 insertion mutations (Ex20ins) are also relatively frequent, accounting for 9% of all EGFR mutations in NSCLC patients.

Patients with EGFR mutations are initially treated with reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib as first-line therapy. However, nearly half of these patients develop acquired resistance to TKI inhibitors by secondary "gatekeeper" T790M mutations within 10-14 months of treatment.

Second-generation EGFR TKIs (eg, afatinib and dacomitinib) have been developed in an attempt to overcome this acquisition resistance mechanism. These agents are irreversible inhibitors that covalently bind to cysteine 797 at the EGFR ATP binding site, which has potent activity against both activation (L858R, ex19del) and acquisition (T790M) EGFR mutations in preclinical models. However, its clinical efficacy has proven to be limited, probably due to the serious adverse effects caused by the simultaneous inhibition of some wild-type (WT) EGFR.

To overcome previous problems with predecessor inhibitors, a third generation EGFR TKI has been developed, which is WT EGFR-preserving but activated EGFR (L858R and ex19del) and acquired (T790M) mutations. Has relatively equivalent efficacy. Third-generation EFGR TKIs such as AZD9291 (meleletinib) and CO-1686 (rosiretinib) are beginning to enter clinical development and show significant early promising (eg, "AZD9291 in EGFR Inhibitor-Resistant Non-Small"). -Cell Lung Cancer ”, Hanne et al., N Engl J Med, 2015; 372; 1689-99 and“ Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer ”, Sequist et al, J Med, 2015; 372; See 1700-9). Also “ASP8273, a novel mutant-selective irreversible EGFR inhibitor, inhibits growth of non-small cell lung cancer (NSCLC) cells with EGFR activating and T790M resistance mutations”, Sakagami et al., AACR; Cancer Res 2014; 74; 1728. See.

Treatment with EGFR inhibitors, however, has not shown a definitive conversion to overall survival, and it is unlikely that third-generation inhibitors alone will suffice. Therefore, there is still a need for additional treatment options for patients with cancer, especially solid tumors. There is also a need for additional treatment options for patients with lung cancer such as NSCLC. One such method that boosts the efficacy of EGFR inhibitors in vivo is by doubly targeting other proteins involved in disease progression in NSCLC patients.

The PD-1 pathway has been described as involved in antigenic escape in a mouse model of EGFR-driven lung tumors (Akbay et al., Cancer Discov. 2013). However, a non-significant trend was also reported for increased PD-L1 levels in NSCLC cell lines derived from EGFR mutant patients. Therefore, it remains unclear whether PD-1 / PD-L1 interactions and targeting of mutant EGFR are safe or clinically important in cancer patients, especially NSCLC patients.

The present invention states that a combination treatment containing the selective mutant EGFR inhibitor EGF816 and the anti-PD-1 antagonist nivolumab is safe and tolerated when administered as a combination therapy to patients with NSCLC having mutant EGFR. Regarding the amazing discovery of.

EGF816 is an EGFR inhibitor. EGF816 is (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) gnat-2-enoyl) azepan-3-yl) -1Hbenzo [d] imidazole-2-yl). ) -2-Methylisonicotinamide (EGF816) or a pharmaceutically acceptable salt thereof. A particularly useful salt is its mesylate. WO 2013/184757, which is incorporated herein by reference, discloses EGF 816, a method thereof and a pharmaceutical composition comprising EGF 816.

EGF816 has the following structure.

EGF816 is a targeted covalently irreversible EGFR inhibitor that selectively inhibits activation and acquisition resistance mutants (L858R, ex19del and T790M) while preserving WT EGFR (Jia et al., Cancer Res). See October 1, 2014 74; 1734)). EGF816 shows significant efficacy in EGFR mutant (L858R, ex19del and T790M) cancer models (in vitro and in vivo) at clinically appropriate effective concentrations without signs of WT EGFR inhibition.

の化合物(Ｒ,Ｅ)－Ｎ－(７－クロロ－１－(１－(４－(ジメチルアミノ)ブト－２－エノイル)アゼパン－３－イル)－１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル)－２－メチルイソニコチンアミド(ＥＧＦ８１６)またはその薬学的に許容される塩および(ｂ)ニボルマブを含む、医薬組み合わせ剤に関する。 In one aspect, the present invention is in formula (a) I.

Compound (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) butto-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole-2- Il) -2-methylisonicotinamide (EGF816) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutical combination comprising nivolumab.

In one aspect, the invention is a combination for use in the treatment of cancer, particularly EGFR mutant cancer.
(i) The combined administration has clinical efficacy, eg, measured at a defined time for disease progression;
(ii) Combined administration has long-lasting clinical benefits; or
(iii) prolong non-progressive survival or provide any combination of the above benefits.

Cancer progression can be monitored by methods known to those of skill in the art. For example, progression can be monitored by visual or tumor biomarker detection methods of cancer, such as by means of x-rays, CT scans or MRI. For example, increased growth of cancer indicates cancer progression. Cancer or tumor progression such as NSCLC can be indicated by detection of new tumors or metastasis or arrest of tumor contraction. Tumor assessment is based on RECIST criteria (Therasse et al. 2000), New Guidelines to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et. al. 2009) European Journal of Cancer; 45: 228-247.

Tumor progression can be determined by comparing the tumor status between the time points after the start of the treatment or by comparing the tumor states after the start of the treatment with those before the start of the associated treatment.

In some embodiments, the lymphoma (eg, anaplastic large cell lymphoma or non-Hodgkin's lymphoma) is identified as having or having an ALK translocation, eg, an EML4-ALK fusion.

In some embodiments, the combination is for use in the treatment of NSCLC.

In some embodiments, the combination is for use in the treatment of NSCLC, which is characterized by one or more of the aberrant activation or amplification or mutation of the epidermal growth factor receptor.

In some embodiments, the combination is for use in the treatment of NSCLC, where NSCLC is characterized by having EGFR exon 20 insertion, EGFR exon 19 deletion, EGFR L858R mutation, EGFR T790M or any combination thereof. ..

In some embodiments, the combination is for use in the treatment of NSCLC, which is characterized by having the L858R and T790M variants of EGFR.

In some embodiments, the combination is for use in the treatment of NSCLC, which is characterized by having an EGFR exon 20 insertion and a T790M mutation in EGFR.

In some embodiments, the combination is for use in the treatment of NSCLC, which is characterized by having an EGFR exon 19 deletion and a T790M mutation.

In some embodiments, the combination is for use in the treatment of NSCLC, where NSCLC comprises an EGFR mutation selected from the group consisting of exon 20 insertion, exon 19 deletion, L858R mutation, T790M mutation and any combination thereof. Characterized by having.

In another embodiment, the cancer is an inflammatory myofibroblast tumor (IMT). In some embodiments, the inflammatory myofibroblast tumor is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion, eg, EML4-ALK fusion.

In yet another embodiment, the cancer is neuroblastoma.

In some embodiments, neuroblastoma is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion, eg, EML4-ALK fusion. The methods and compositions disclosed herein are useful in the treatment of metastatic lesions associated with said cancer.

EGF816 can be administered at doses of 75 mg, 100 mg, 150 mg, 225 mg, 150 mg, 200 mg, 225 mg, 300 mg or 350 mg. These doses may be administered once daily. For example, EGF816 can be administered at a dose of 100 mg or 150 mg once daily.

Nivolumab may be administered at about 1 mg / kg to 5 mg / kg, eg, 3 mg / kg, and may be administered approximately once a week for 2 weeks, 3 weeks or 4 weeks for a period of 60 minutes. ..

In some embodiments, the combination of EGF816 and nivolumab is administered as a combination therapy and the dosing protocol is
(i) 150 mg of (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole -2-Il) -2-Methylisonicotinamide or a pharmaceutically acceptable salt thereof is orally administered daily; and
(ii) Intravenous administration of 3 mg / kg nivolumab every 2 weeks for 60 minutes at least 1 hour after administration of (i).

In some embodiments, the dosing protocol is repeated for a period of 28-day cycles.

As used herein, the term "pharmaceutical combination" means a product that is a mixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of these active ingredients. The term "fixed combination" means that these active ingredients, eg, a compound of formula (I) and one or more combination partners, are both administered to a patient simultaneously as one or as a dose. The term "unfixed combination" refers to these active ingredients, eg, compounds of the invention and one or more combination partners, both as separate to the patient, simultaneously, together or without specific time limit. Means to be administered to, such administration provides a therapeutically effective level of the two compounds in the patient's body. The latter also applies to cocktail therapy, eg administration of 3 or more active ingredients.

The present invention provides each of the aspects, advantageous properties and specific embodiments listed in the following enumeration embodiments, either alone or in combination.

の化合物(Ｒ,Ｅ)－Ｎ－(７－クロロ－１－(１－(４－(ジメチルアミノ)ブト－２－エノイル)アゼパン－３－イル)－１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル)－２－メチルイソニコチンアミドまたはその薬学的に許容される塩
および(ｂ)ニボルマブ
を含む、医薬組み合わせ剤。 Enumeration mode:
1. (a) Equation I

Compound (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole-2- Il) -2-Methylisonicotinamide or a pharmaceutically acceptable salt thereof and (b) a pharmaceutical combination comprising nivolumab.

1. (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) butto-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole-2- Il) -2-Methylisonicotinamide is a mesylate form or a hydrochloride form, the pharmaceutical combination according to the enumerated embodiment 1.

2. A pharmaceutical composition comprising an enumeration embodiment 1 or a combination according to enumeration embodiment 2 and at least one pharmaceutically acceptable carrier.

3. The pharmaceutical combination drug according to any one of the enumeration embodiments 1 to 3 and the composition of the pharmaceutical combination drug are used simultaneously, separately or sequentially, and / or the pharmaceutical combination drug according to any one of the enumeration embodiments 1 to 3. A kit containing information indicating that the constituents of the drug should be administered simultaneously, separately or sequentially.

4. A method for treating or preventing cancer in a subject in need of treatment, according to any of the listed embodiments 1 to 3 (R, E) -N- (7-chloro-1- (1- (4- (4- (4- (4-). (Dimethylamino) butto-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazol-2-yl) -2-methylisonicotinamide or a pharmaceutically acceptable salt thereof and nivolumab. Methods that include sequential, simultaneous or separate administration of therapeutically effective doses in combination for the treatment or prevention of cancer.

5. (a) 1 or more dose units of (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) butto-2-enoyl) azepan-3-yl) -1H -A form of a kit for combined administration comprising benzo [d] imidazol-2-yl) -2-methylisonicotinamide or a pharmaceutically acceptable salt thereof and (b) one or more dose units of nivolumab. A pharmaceutical combination agent according to any one of the listed embodiments 1 to 3.

6. (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) butto-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole-2- Il) -2-methylisonicotinamide and nivolumab administered simultaneously, sequentially or separately, for use in the treatment of cancer, a pharmaceutical combination according to any of the listed embodiments 1 to 3 or the enumerated embodiments 4 or Kit according to enumeration embodiment 6.

7. A pharmaceutical combination according to any of the enumeration embodiments 1 to 3 or a kit according to the enumeration embodiment 4 or 6 for use according to the enumeration embodiment 7, wherein the cancer is non-small cell lung cancer.

8. Listed Aspects 1-to be used by any of Enumeration Aspects 7 or 8 where non-small cell lung cancer is characterized by aberrant activation or amplification or mutation (EGFR) of the epidermal growth factor receptor. A pharmaceutical combination according to any one of 3 or a kit according to the enumeration mode 4 or the enumeration mode 6.

9. Used by any of the enumerated embodiments 7-9 characterized by non-small cell lung cancer having EGFR exon 20 insertion, EGFR exon 19 deletion, EGFR L858R mutation, EGFR T790M or any combination thereof. A pharmaceutical combination agent according to any one of the enumeration modes 1 to 3 or a kit according to the enumeration mode 4 or the enumeration mode 6 for the purpose.

10. Pharmaceutical combination or enumeration according to any of enumeration embodiments 1-3 for use according to any of enumeration embodiments 7-9, characterized by non-small cell lung cancer having L858R and T790M variants of EGFR. Kit according to aspect 4 or enumeration aspect 6.

11. Pharmaceutical combination according to any of the enumeration embodiments 1-3 for use according to any of the enumeration embodiments 7-9, characterized by non-small cell lung cancer having an exon 20 insertion of EGFR and a T790M mutation. Or a kit according to enumeration mode 4 or enumeration mode 6.

12. Pharmaceutical combination according to any of enumeration embodiments 1-3 for use by any of enumeration embodiments 7-9, characterized by non-small cell lung cancer having an exon 19 deletion of EGFR and a T790M mutation. Agent or kit according to enumeration embodiment 4 or enumeration embodiment 6.

13. Listed embodiments 7-9 characterized by non-small cell lung cancer having an exon 20 insertion, an exon 19 deletion, an L858R mutation, a T790M mutation and an EGFR mutation selected from the group consisting of any combination thereof. A pharmaceutical combination according to any of the enumeration embodiments 1 to 3 or a kit according to the enumeration embodiment 4 or the enumeration embodiment 6 for use according to any of the above.

14. A pharmaceutical combination according to any of the enumeration embodiments 1-3 or 4 for use according to any of the enumeration embodiments 7-14, wherein the combination combination is administered within a specific time period and the combination is administered for a certain period of time. Agent or kit according to enumeration embodiment 6.

15. The combination was administered according to enumeration embodiment 15 and (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl) -1H. -The amount of benzo [d] imidazol-2-yl) -2-methylisonicotinamide or a pharmaceutically acceptable salt thereof is about 50-500 mg every other day, every day, twice or three times a day, preferably. 75 mg, 100 mg, 150 mg, 225 mg, 150 mg, 200 mg, 225 mg, 300 mg or 350 mg, more preferably 150 mg. Pharmaceutical combination agent or kit according to enumeration embodiment 6.

16. The combination was administered according to enumeration embodiment 15 and (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl) -1H. -The amount of benzo [d] imidazol-2-yl) -2-methylisonicotinamide or a pharmaceutically acceptable salt thereof is about 50 to about 225 mg, preferably about 100 to about 150 mg, administered daily. A pharmaceutical combination according to any of the enumeration embodiments 1 to 3 or the enumeration embodiment 4 or a kit according to the enumeration embodiment 6 for use according to any of the enumeration embodiments 7 to 14, preferably 150 mg.

17. The combination is administered according to enumeration embodiment 15, and the amount of nibolumab is from about 1 mg / kg to about 5 mg / kg, preferably 3 mg / kg, approximately once to 2 weeks, 3 weeks or 4 per week. A pharmaceutical combination or enumeration according to any of enumeration embodiments 1-3 or 4 for use by any of enumeration embodiments 7-14, which is administered non-enteric once a week for a time of 60 minutes. Kit according to aspect 6.

18. The combination is administered according to enumeration embodiment 15 and (i) (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl). ) -1H-benzo [d] imidazole-2-yl) -2-methylisonicotinamide or a pharmaceutically acceptable salt thereof in an amount of about 50 to about 500 mg, preferably about 75 mg, 100 mg, 150 mg, 225 mg, 150 mg, 200 mg, 225 mg, 300 mg or 350 mg, more preferably 150 m, administered daily, (ii) the amount of nivolumab is from about 1 mg / kg to about 5 mg / kg, preferably 3 mg / kg. , Enumeration embodiments 1 to 14 for use according to any of enumeration embodiments 7-14, which are administered non-enteric for a period of 60 minutes and are administered every 2 weeks for 12 days or more during each treatment. A pharmaceutical combination according to any one of 3 or a kit according to the enumerated embodiment 6.

19. Nivolumab, (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) gnat-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole -2-Il) -2-Methylisonicotinamide A pharmaceutical combination according to any of the listed embodiments 15 to 20, which is administered at least 1 hour after administration.

20. (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) butto-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole-2- Ill) -2-Methylisonicotinamide or a pharmaceutically acceptable salt thereof and a pharmaceutical combination according to enumeration embodiments 1 to 3 for use according to any of enumeration embodiments 7 to 14, or enumeration embodiments 4. Alternatively, the administration protocol of the kit according to any of the enumerated embodiments 6 is
(i) 150 mg of (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl) -1H-benzo [d] imidazole -Daily oral administration of -2-yl) -2-methylisonicotinamide or a pharmaceutically acceptable salt thereof; and
(ii) Intravenous administration of 3 mg / kg nivolumab every 2 weeks for 60 minutes at least 1 hour after administration of (i).
including.

21. The dosing protocol according to enumeration embodiment 21, wherein the protocol is repeated for one or more periods of a 28-day cycle.

Pharmaceutical Compositions and Kits In other aspects, the invention provides compositions comprising the antibody molecules described herein, eg, pharmaceutically acceptable compositions, formulated with a pharmaceutically acceptable carrier. .. The term "pharmaceutically acceptable" is used in contact with human and animal tissues with reasonable benefit / risk ratios without excessive toxicity, irritation, allergic response or other problems or complications. Suitable for compounds, substances, compositions and / or dosage forms.

The "pharmaceutically acceptable carrier" used herein includes any and all solvents, dispersion media, isotonic and absorption retarders, etc. that are physiologically compatible. The carrier is suitable for intravenous, intramuscular, subcutaneous, non-enteral, rectal, spinal or epithelial administration (eg by injection or infusion).

The pharmaceutically acceptable salt can be formed, for example, as an acid addition salt, preferably an organic or inorganic acid. Suitable inorganic acids are halogenic acids such as hydrochloric acid, for example. Suitable organic acids are, for example, carboxylic acids or sulfonic acids such as fumaric acid or methanesulfonic acid. It is also possible to use pharmaceutically unacceptable salts such as picrates or perchlorates for isolation or purification purposes. For therapeutic use, pharmaceutically acceptable salts or free compounds (if applicable in the form of pharmaceutical formulations) can be used and are therefore preferred. In view of the close relationship between the novel compounds in free form and those in the form of salts thereof, including those salts that can be used as intermediates, for example in the purification or identification of novel compounds, supra and later herein. Any reference to a free compound of is to be understood to also refer to the corresponding salt, where appropriate and convenient. The salts of the compounds described herein are preferably pharmaceutically acceptable salts, and pharmaceutically acceptable salts that form suitable counterions are known in the art.

The compositions of the present invention can be in various forms. These include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (eg, injectable and injectable solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended dosing method and therapeutic application. Typical preferred compositions are injectable and injectable solutions. The preferred method of administration is non-enteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody is administered by intravenous drip or injection. In another preferred embodiment, the antibody is administered by intramuscular or subcutaneous injection.

The pharmaceutical composition can be made with a pharmaceutically acceptable carrier, which can be, for example, any suitable pharmaceutical additive. Carriers, as known to those of skill in the art, are any and all binders, fillers, solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial agents, antifungal agents), Includes isotonics, absorption retarders, salts, drug stabilizers, disintegrants, lubricants, sweeteners, flavors, pigments, etc. and combinations thereof (eg, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329; Remington: The Science and Practice of Pharmacy, 21st Ed. Pharmaceutical Press 2011; and subsequent editions). Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is intended. Other disclosures herein relating to pharmaceutical compositions can also be made.

INDUSTRIAL APPLICABILITY According to the present invention, the combination partners can be administered independently, simultaneously or separately within a certain time interval, in different unit dosage forms. Both treatment partners may be prepared by methods known per se and for enteral, eg, oral or rectal, topical and non-enteral administration to subjects in need thereof, including warm-blooded animals, especially humans. Suitable. Suitable pharmaceutical compositions include, for example, about 0.1% to about 99.9% active ingredient.

The pharmaceutical composition can be processed to produce the final dose formulation-tablets or capsules. This can be achieved by compressing the final mixture of combinations with one or more additives, if desired. Compression can be achieved, for example, with a rotary locker. Tablets of various shapes can be produced (round, oval or other suitable form). Tablets may or may not be coated by known techniques, delaying disintegration and absorption in the gastrointestinal tract, thereby sustaining long-term action. Unless otherwise noted, they are produced by methods known per se, for example by means of mixing, granulation, sugar coating. Formulations for oral use include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or cellulose-based additives, or the active ingredient in a water or oil medium, such as olive oil, liquid paraffin. Alternatively, it is provided as a soft gelatin capsule mixed with peanut oil.

As used herein, the terms "non-enteral administration" and "non-enteral administration" refer to methods of administration by conventional injection other than enteral and topical administration, including intravenous, intramuscular, and intraarterial. Includes intrathecal, intracapsular, intraocular, intracardiac, intracutaneous, intraperitoneal, enteral, subcutaneous, subepithelial, intra-articular, subcapsular, subspider, intraspinal, epidural and intrathoracic injections and infusions. However, it is not limited to these.

The therapeutic composition should be generally sterile and stable under manufacturing and storage conditions. The composition can be formulated as a solution, microemulsion, dispersion, liposome or other ordered structure suitable for high antibody concentrations. The sterile injectable solution can be formulated by incorporating the required amount of the active compound (ie, antibody or antibody portion) into a suitable solvent, optionally with one or a combination of the above listed components, followed by filtration sterilization. .. Dispersions are generally made by incorporating the active compound into a sterile medium containing the basic dispersion medium and other necessary components from those listed above. For sterile powders for the production of sterile injectable solutions, preferred production methods are vacuum drying and lyophilization to obtain powders of any additional desired ingredients in addition to the active ingredients from the pre-sterile filtered solution. Proper fluidity of the solution can be maintained, for example, by the application of a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by the use of surfactants. Extended absorption of the injectable composition can be achieved by including the composition with agents that delay absorption, such as monostearate and gelatin.

The antibody molecule can be administered by a variety of methods known in the art, but for many therapeutic applications, the preferred route / method of administration is intravenous injection or infusion. For example, the antibody molecule is administered by intravenous drip slower than 10 mg / min; preferably at a rate of 5 mg / min or less, about 1-100 mg / m ² , preferably about 5-50 mg / m ² , about 7. A dose of ~ 25 mg / m ² , more preferably about 10 mg / m ² can be achieved. As will be appreciated by those of skill in the art, the route of administration and / or the method of administration will vary depending on the desired outcome. In some embodiments, the active compound may be controlled with a carrier that protects the compound from rapid release, such as a controlled release formulation, including implants, transdermal patches and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acids, collagens, polyorthoesters and polylactic acids can be used. Many methods of making such formulations have been patented or are generally known to those of skill in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In some embodiments, the antibody molecule can be orally administered, for example, with an inert diluent or an absorbable edible carrier. Compounds (and, if desired, other ingredients) may also be filled into hard or soft-shell gelatin capsules, compressed into tablets, or included directly in the diet of interest. For oral therapeutic administration, compounds may be included with additives and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. In order to administer the compound of the invention other than non-intestinal administration, it may be necessary to coat the compound with a substance that inhibits its inactivation or co-administer the compound. Therapeutic compositions can also be administered using medical devices known in the art.

The dosing regimen is adjusted to provide the optimal desired response (eg, therapeutic response). For example, a single bolus may be administered, a divided dose may be administered over time, or the dose may be reduced or increased correspondingly, depending on the urgent demands of the treatment situation. Due to ease of administration and dose uniformity, it is particularly advantageous to formulate the non-enteral composition in dose unit form. The dose unit form used herein refers to physically separate units suitable as unit doses for the subject to be treated, each unit, together with the required pharmaceutical carrier, to be calculated to produce the desired therapeutic effect. Contains the amount of active compound. The specifications of the dose unit form of the present invention are limited and directly limited by (a) the specific properties of the active compound and the particular therapeutic effect to be achieved and (b) the conditions specific to the active compound for treatment susceptibility in the individual. It depends on this.

The term "effective amount" is a subject capable of producing the biological or medical response in cells, tissues, organs, systems, animals or humans sought by researchers, veterinarians, physicians or other clinicians. The amount of compound. The effective dose of each combination partner agent used in the combinations disclosed herein may vary depending on the particular compound or pharmaceutical composition used, the method of administration, the condition being treated, and the severity of the condition being treated. A normally proficient physician, clinical worker or veterinarian can easily determine and prescribe the effective amount of drug required to prevent, reverse or stop progression of the condition. Optimal accuracy to achieve effective drug concentrations requires a regimen based on the dynamics of combined drug availability at the target site. This includes consideration of drug distribution, equilibrium and excretion.

"Therapeutically effective amount" means an amount that is effective at the dosage and duration required to achieve the desired therapeutic result. The therapeutically effective amount of a modified antibody or antibody fragment may vary depending on factors such as the disease state, age, sex and body weight of the individual and the antibody or antibody moiety that elicits the desired response in the individual. A therapeutically effective amount is also an amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the modified antibody or antibody fragment. The "therapeutically effective dose" is preferably a measurable parameter, eg, a tumor growth rate of at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, as compared to the untreated subject. Even more preferably, it blocks at least about 80%. The measurable parameters of a compound, eg, its ability to inhibit cancer, can be assessed in an animal model system that is a predictor of efficacy in human tumors. Alternatively, this property of the composition can be assessed by testing the ability of the compound to inhibit in vitro by an assay known to those of skill in the art.

"Prophylactically effective amount" means an amount that is effective at the dosage and duration required to achieve the desired prophylactic result. Generally, the prophylactic dose is less than the therapeutically effective dose because the prophylactic dose is used for subjects in the early stages of the disease or earlier.

Methods of administering antibody molecules are known in the art and are described below. The appropriate dose of the molecule used depends on the age and weight of the subject and the particular drug used. The dosage and treatment regimen of the anti-PD-1 antibody molecule can be determined by those of skill in the art. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 1-30 mg / kg, eg, about 5-25 mg / kg, about 10-20 mg / kg, about 1-5 mg / kg or about 3 mg / kg. Administer by injection (eg, subcutaneously or intravenously). The dosing schedule can vary from once a week to once every two weeks, three or four weeks. In some embodiments, the anti-PD-1 antibody molecule is administered biweekly at a dose of about 10-20 mg / kg.

An exemplary, non-limiting range of therapeutically or prophylactically effective amounts of antibody molecules is 0.1-30 mg / kg, more preferably 1-25 mg / kg. The dosage and treatment regimen of the anti-PD-1 antibody molecule can be determined by one of ordinary skill in the art. In some embodiments, the anti-PD-1 antibody molecule is about 1-30 mg / kg, eg, about 5-25 mg / kg, about 10-20 mg / kg, about 1-5 mg / kg, 1-10 mg / kg, 5- Administer by injection (eg, subcutaneously or intravenously) at doses of 15 mg / kg, 10-20 mg / kg, 15-25 mg / kg or about 3 mg / kg. The dosing schedule can vary from once a week to once every two weeks, three or four weeks. In some embodiments, the anti-PD-1 antibody molecule is administered biweekly at a dose of about 10-20 mg / kg. The antibody molecule is administered by intravenous infusion at a rate slower than 10 mg / min, preferably 5 mg / min or less, to about 1-100 mg / m ² , preferably about 5-50 mg / m ² , about 7-25 mg. A dose of / m ² and more preferably about 10 mg / m ² can be achieved. It should be noted that dose values may vary depending on the type and severity of the condition to be alleviated. In addition, certain subjects, specific dose regimens should be adjusted over time at the discretion of those who administer or monitor administration of individual requirements and compositions, and the dose ranges shown herein are merely. It should also be noted that this is an example and does not limit the scope or practice of the claimed composition.

The antibody molecule can be used on its own or conjugated to a second agent such as a cytotoxic agent, radioisotope or protein, such as a protein toxin or viral protein. The method comprises administering the antibody molecule alone or in combination with a cytotoxic agent to a subject in need of such treatment. Antibody molecules can be used in a variety of therapeutic agents, such as cytotoxic moieties, such as therapeutic agents, radioactive isotopes, plant, fungal or bacterial origin molecules or biological proteins (eg, protein toxins) or particles (eg, recombinant viruses). Particles, eg; via virus-coated proteins) or mixtures thereof, can be delivered.

Also within the scope of the present invention is a kit comprising the combination therapies described herein. Kits are instructions for use; other reagents, such as labels, therapeutic agents or agents useful for chelating or coupling to others, labeling antibodies or therapeutic agents or radioprotective compositions; preparing antibodies for administration. A device or other device for; a pharmaceutically acceptable carrier; and one or more other elements, including a device or other substance for administration to a subject.

Use of Combination Therapies The combination therapies disclosed herein have in vitro and in vivo therapeutic and prophylactic usefulness. For example, these molecules can be administered to cultured cells in vitro or in Exvivo or to a subject, eg, a human subject, to treat, prevent and / or diagnose a variety of disorders such as cancer.

As used herein, the terms "treatment" and "treat" are disorders resulting from the administration of one or more treatments (eg, one or more therapeutic agents such as the combination therapy disclosed herein), eg, proliferative disorders. A reduction or amelioration or impairment of progression (eg, cancer), severity and / or duration, eg, improvement of one or more symptoms (preferably one or more recognizable symptoms) of proliferative disorders. In certain embodiments, the terms "treatment" and "treating" are at least one measurable body of a proliferative disorder (eg, cancer) such as tumor growth that is not necessarily recognizable by the subject, eg, the patient. Refers to the improvement of parameters. In other embodiments, the terms "treatment" and "treatment" are used to prevent the progression of proliferative disorders by physical, eg, recognizable symptom stabilization, physiological, eg, physical parameter stabilization, or both. say. In other embodiments, the terms "treatment" and "treating" refer to reducing or stabilizing tumor size or cancerous cell count.

In some embodiments, amelioration of a disorder comprises one or more that delays, stops or alleviates the progression of at least one of the disease or its clinical symptoms to prevent or delay the onset, progression or progression of the disease or disorder. In addition, these terms alleviate or improve at least one physical parameter that may not be recognizable to the patient and also physical (eg, recognizable symptom stabilization), physiological (eg, physical parameter stabilization) or It also refers to the regulation of disease or disorder by both.

The term "treatment" includes, for example, therapeutic administration of one or more of the combination therapies disclosed herein to a subject, eg, a warm-blooded animal, particularly a human, in need of such treatment. In some embodiments, the treatment is aimed at curing the disease or has an effect on disease regression or delay in disease progression.

The term "object" as used herein is intended to include humans and non-human animals. In some embodiments, the subject is a human subject, eg, a human patient with a disorder or condition characterized by abnormal cell proliferation and / or immune function. The term "non-human animal" includes mammals such as non-human primates and non-mammals. In some embodiments, the subject is a human. In some embodiments, the subject is a human patient in need of an enhanced immune response. The term "subject in need of treatment" is a warm-blooded animal, especially a human, who will benefit from the treatment biologically, medically or quality of life. In some embodiments, the subject is immune impaired, eg, the subject is receiving or has received chemotherapy or radiation therapy. Apart from or in addition to this, the subject is at or at risk of immunodeficiency as a result of infection. The methods and compositions described herein are suitable for the treatment of human patients with disorders that can be treated by enhancing the T cell-mediated immune response. For example, the methods and compositions described herein can enhance a large number of immune activities. In some embodiments, the subject has an increased number or activity of tumor-infiltrating T lymphocytes (TIL). In another embodiment, the subject has increased expression or activity of interferon-gamma (IFN-γ). In yet another embodiment, the subject has reduced PD-L1 expression or activity.

Accordingly, in one aspect, the invention provides a method of modifying an immune response in a subject, comprising administering to the subject the antibody molecule described herein such that the immune response in the subject is modified. In some embodiments, the immune response is enhanced, stimulated or upregulated. In some embodiments, the antibody molecule enhances an immune response in a subject by blocking a checkpoint inhibitor (eg, PD-1, PD-L1, LAG-3 or TIM-3).

Blocking a cancer checkpoint inhibitor, such as PD-1, can enhance the immune response to cancerous cells in a subject. PD-L1, a ligand for PD-1, is not expressed in normal human cells, but is abundant in a variety of human cancers (Dong et al. (2002) Nat Med 8: 787-9). The interaction of PD-1 and PD-L1 can result in decreased tumor infiltrating lymphocytes, T cell receptor-mediated proliferation and / or reduced immune avoidance by cancerous cells (Dong et al. (2003) J Mol Med). 81: 281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54: 307-314; Konishi et al. (2004) Clin. Cancer Res. 10: 5094-100).

In one aspect, the invention describes immunomodulatory, eg, anti-PD-1 or anti-PD-L1 antibody molecules, alone or herein so as to inhibit or reduce the growth of cancerous tumors. It relates to a method of treating a subject in vivo for use in combination with an agent. Immunomodulators can be used alone to inhibit the growth of cancerous tumors. Alternatively, anti-PD-1 or anti-PD-L1 antibodies are disclosed in Table 1, standard therapeutic treatments (eg, for cancer), other antibodies or antigen-binding fragments thereof, other immunomodulators (eg, co-stimulation). A sex molecule activator or inhibitory molecule inhibitor); a vaccine, eg, a therapeutic cancer vaccine; or can be used in combination with one or more of other forms of cellular immunotherapy, such as:

Thus, in certain embodiments, the invention provides a method of inhibiting the growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of the combination therapy disclosed herein. In some embodiments, the method is suitable for treating cancer in vivo. When an antibody against PD-1 is administered in combination with one or more drugs, the combination may be administered in any order or at the same time.

In other aspects, methods are provided for treating a subject, eg, reducing or ameliorating a proliferative condition or disorder (eg, cancer), eg, a solid tumor, soft tissue tumor or metastatic lesion in the subject. The method presents a subject with one or more immunomodulators, eg, anti-PD-1 or PD-L1 antibody molecules described herein, alone or with other agents or therapeutic modality (eg, one or more from Table 1). Includes administration in combination with (drugs).

As used herein, the term "cancer" includes all types of cancerous growth or carcinogenic processes, metastatic or malignant transformed cells, tissues or organs, regardless of histopathological type or invasive stage. Examples of cancerous disorders include, but are not limited to, solid tumors, soft tissue tumors and metastatic lesions. Examples of solid tumors are diverse organ systems such as those affecting the liver, lungs, breasts, lymphatic system, digestive system (eg colon), urogenital organs (eg kidney, urinary tract epithelial cells), prostate and pharynx. Malignant tumors, including, but not limited to, sarcomas, adenocarcinomas and carcinomas. Adenocarcinoma includes most malignant tumors such as colon cancer, rectal cancer, renal cell cancer, liver cancer, lung non-small cell cancer, small intestine cancer and esophageal cancer. In some embodiments, the cancer is melanoma, eg, advanced stage melanoma. The metastatic lesions of the cancer can also be treated or prevented using the methods and compositions of the present invention.

Examples of cancers that can block growth with the antibody molecules disclosed herein generally include cancers that are responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment are melanoma (eg, metastatic malignant melanoma), kidney cancer (eg, clear cell cancer), prostate cancer (eg, hormone refractory prostate adenocarcinoma), breast cancer, colon. Includes cancer and lung cancer (eg, non-small cell lung cancer). In addition, refractory or recurrent malignancies can be treated with the antibody molecules described herein.

Examples of other cancers that can be treated are bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastroesophageal cancer, gastric cancer, testicular cancer. , Uterine cancer, Faropius tube cancer, Endometrial cancer, Cervical cancer, Vaginal cancer, Eccentric cancer, Hodgkin's disease, Non-Hojikin's lymphoma, Esophageal cancer, Small intestinal cancer, Endocrine cancer Of soft tissue sarcoma, urinary tract cancer, penis cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic or acute leukemia including chronic lymphocytic leukemia, pediatric solid tumor, lymphatic lymphoma, bladder cancer, kidney or urinary tract Cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenomas, caposic sarcoma, epidermoid cancer, squamous cell carcinoma, T-cell lymphoma , Including environment-induced cancers and combinations of the cancers, including those induced by asbestos.

Treatment of metastatic cancers, such as metastatic cancers expressing PD-L1 (Iwai et al. (2005) Int. Immunol. 17: 133-144), can be performed using the antibody molecules described herein. In some embodiments, the cancer expresses high levels of PD-L1, IFNγ and / or CD8.

A hematological cancer state is a type of cancer that affects the blood, bone marrow, and lymphatic system, such as leukemia and malignant lymphoproliferative states. Leukemia can be classified as acute leukemia and chronic leukemia. Acute leukemia can be further classified as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Chronic leukemias include chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL). Another related condition is myelodysplastic syndrome (MDS, formerly "previous", which is a diverse collection of hematological conditions summarized by dysplasia (or dysplasia) of bone marrow blood cells and the risk of transformation to AML. Includes (known as "leukemia").

In other embodiments, the cancer is a cancer including, but not limited to, hematopoietic tumors or leukemias or lymphomas. For example, using combination therapy, including, but not limited to, B-cell acute lymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia (“TALL”), acute lymphoid leukemia (ALL). , For example, acute leukemia; eg, one or more chronic leukemias including, but not limited to, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL); eg, pre-B cell lymphocytic leukemia, blastic traits. Cell-like dendritic cell neoplasm, Berkit lymphoma, generalized large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative state, MALT lymphoma, mantle cell lymphoma, Peripheral leukemia, multiple myeloma, myeloid dysplasia and myeloid dysplasia syndrome, non-hodgkin lymphoma, plasmablastic lymphoma, leukemia-like dendritic cell neoplasm, Waldenstrem macroglobulinemia and myeloid hematology Cancers including, but not limited to, further hematological or hematological conditions, including, but not limited to, "pre-leukemia", a diverse collection of hematological conditions summarized by production deficiency (or dysplasia). And can treat malignant tumors. In some embodiments, the lymphoma (eg, anaplastic large cell lymphoma or non-Hodgkin's lymphoma) is identified as having or having an ALK translocation, eg, an EML4-ALK fusion.

In some embodiments, the cancer is lung cancer (eg, non-small cell lung cancer (NSCLC) (eg, NSCLC with squamous epithelium and / or non-splasia epithelial histology)), melanoma (eg, advanced melanoma), kidney. Cancer (eg, renal cell carcinoma, eg, clear cell renal cell carcinoma), liver cancer, myeloma (eg, multiple myeloma), prostate cancer, breast cancer (eg, estrogen receptor, progesterone receptor or Her2 / neu) Cancers that do not develop one, two or all, such as triple negative breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC), anal cancer, gastroesophageal cancer, thyroid cancer, It is selected from cervical cancer, lymphoproliferative disorder (eg, post-implantation lymphoproliferative disorder) or hematological cancer, T-cell lymphoma, non-Hodgkin lymphoma or leukemia (eg, myeloid leukemia).

In other embodiments, the cancer is selected from cancer (eg, advanced or metastatic cancer), melanoma or lung cancer, eg, non-small cell lung cancer.

In some embodiments, the cancer is lung cancer, eg, non-small cell lung cancer (NSCLC). In some embodiments, lung cancer, eg, non-small cell lung cancer, is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion, eg, EML4-ALK fusion.

In another embodiment, the cancer is an inflammatory myofibroblast tumor (IMT). In some embodiments, the inflammatory myofibroblast tumor is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion, eg, EML4-ALK fusion.

In another embodiment, the cancer is NSCLC, which is characterized by one or more of the aberrant activation, amplification or mutation of the epidermal growth factor receptor (EGFR). In some embodiments, the cancer is NSCLC, which is characterized by having EGFR exon 20 insertion, EGFR exon 19 deletion, EGFR L858R mutation, EGFR T790M or any combination thereof. In some embodiments, NSCLC is characterized by having the L858R and T790M variants of EGFR. In some embodiments, NSCLC is characterized by having an EGFR exon 20 insertion and a T790M mutation in the EGFR. In some embodiments, NSCLC is characterized by having an EGFR exon 19 deletion and a T790M mutation in EGFR. In some embodiments, NSCLC is characterized by having an EGFR mutation selected from the group consisting of exon 20 insertion, exon 19 deletion, L858R mutation, T790M mutation and any combination thereof.

In yet another embodiment, the cancer is neuroblastoma.

In some embodiments, neuroblastoma is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion, eg, EML4-ALK fusion. The methods and compositions disclosed herein are useful in the treatment of metastatic lesions associated with said cancer.

In another embodiment, the cancer is hepatocellular carcinoma with or without viral infection, eg, chronic viral hepatitis, eg, advanced hepatocellular carcinoma.

In another aspect, the cancer is prostate cancer, eg, advanced prostate cancer.

In yet another embodiment, the cancer is myeloma, eg multiple myeloma.

In yet another embodiment, the cancer is renal cell carcinoma, eg, renal cell carcinoma (RCC) (eg, metastatic RCC or clear cell renal cell carcinoma).

In some embodiments, the cancer is melanoma, eg, advanced melanoma. In some embodiments, the cancer is advanced or unresectable melanoma that does not respond to other treatments. In another embodiment, the cancer is a melanoma with a BRAF mutation (eg, BRAF V600 mutation). In yet another embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered after treatment with an anti-CTLA-4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib). ..

In another embodiment, the cancer is an inflammatory myofibroblast tumor (IMT). In some embodiments, the inflammatory myofibroblast tumor is identified as having or having an ALK rearrangement or translocation, eg, ALK fusion, eg, EML4-ALK fusion.

The methods and compositions disclosed herein are useful in the treatment of metastatic lesions associated with said cancer.

Further Combination Therapies The combination therapies disclosed herein are further co-prepared with one or more additional therapeutic agents, such as one or more anticancer agents, cytotoxic or cell proliferation inhibitors, hormone treatments, vaccines and / or other immunotherapies. And / or can be co-administered. In other embodiments, the antibody molecule is administered in combination with other therapeutic treatment modalities, including surgery, radiation, cryosurgery and / or hyperthermia. Such combination therapies advantageously utilize low doses of administered therapeutic agents, thus avoiding the potential for toxicity or complications associated with a variety of monotherapy.

For example, the combination therapies disclosed herein may also be combined with standard cancer treatments. For example, PD-1 blockade can be efficiently combined with a chemotherapeutic regimen. In these cases, it is possible to reduce the dose of chemotherapeutic agent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). In certain embodiments, the methods and compositions described herein can be used with other antibody molecules, chemotherapy, other anti-cancer treatments (eg, targeted anti-cancer treatments or tumor lytic agents), cytotoxic agents, immune-based therapies (eg, targeted anti-cancer treatments or tumor lytic agents). For example, cytokines), surgical and / or applied in combination with one or more of the treatment methods. Examples of cytotoxic agents that can be administered in combination are microtubule inhibitors, topoisomerase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, binca alkaloids, inserts, agents that can interfere with signaling pathways. Includes agents that promote apoptosis, proteosome inhibitors and radiation (eg, local or systemic irradiation).

Examples of combinations with standard of care for cancer include at least:

In certain embodiments, the combination treatments include anastrozole (Arimidex®), vicartamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myrelan®), busulfan injection ( Busulfex®), capecitarabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocitidine, carboplatin (paraplatin®), carmustin (BiCNU®), chlorambusyl (Lukelan®), Sisplatin (Platinol®), Cladribine (Lyostatin®), Cyclophosphamide (Citoxan® or Neosar®), Cytarabine, Citocin arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®) )), Daunorubicin cytarabine liposome injection (DaunoXome®), dexamesazone, docetaxel (taxotere®), doxorubicin hydrochloride (adriamycin®, rubex®), etopocid (vepside®) ), Fludarabin phosphate (Fludara®), 5-fluorouracil (Adrucil®, Fdex®), Flutamide (Eulexin®), tezacitibin, gemcytarabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idalbisin (Idamicin®), Iphosphamide (IFEX®), Irinotecan (Camptosar®), L-asparaginase (Elsper®), Leucovorin calcium, Mel Faran (Alkeran®), 6-mercaptopurine (Purinesol®), Metotrexate (Folex®), Mitoxanthron (Novantron®), Mylotarg, Paclitaxel (Taxol®) ), Nab-paclitaxel (Abraxane®), phoenix (Ittrium 90 / MX-DTP) A), pentostatin, polyfeprosan 20 with carmustine implants (Griadel®), tamoxiphene citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamin (Tirazone®), topotecan hydrochloride for injection (Hycamtin®), vinblastine (Velban®), vincristine (Oncovin®) and vinorelbine (Navelbine®), but Used in combination with standard cancer therapeutic chemotherapeutic agents, not limited to these.

Examples of alkylating agents are nitrogen mustard, ethyleneimine derivatives, alkylsulfonates, nitrosophamides and triazenes): uracil mustard (aminouracil mustard®, Chlorethaminacil®, Demethyldopan®, desmethyldopa (R), Haemanthamine (R), Nordopan (R), Urasyl Nitrogen Mustard (R), Uracillost (R), Uracilmostaza (R), Uramustin (R), Uramstin (R)) , Chlormethin (Mustargen®), Cyclophosphamide (Citoxan®, Neosar®, Clafen®, Endoxan®, Procitox®, Revimmune ^TM ), Iphosphamide (Mitoxana®), Melfaran (Alkeran®), Chlorambusil (Lukelan®), Pipobroman (Amedel®, Vercyte®), Triethylenemelamine (Hemel®) ), Hexalen®, Hexastat®), Triethylenethiophosphoramine, Temozoromide (Temodar®), Thiotepa (Thioplex®), Busulvex®, Myrelan Includes (Registered Trademarks)), Carmustin (BiCNU®), Romustin (CeeNU®), Streptosocin (Zanosar®) and Dacarbazine (DTIC-Dome®). Not limited. Examples of additional alkylating agents are known as oxaliplatin (Eloxatin®); temozolomid (Temodar® and Temodal®); dactinomycin (actinomycin-D, Cosmegen®). ); Melfaran (also known as L-PAM, L-sarcolicin and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU (registered)) Bendamustine (Treanda®); Busulfan (Busulfex® and Myrelan®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®) Lomustine (CDDP, Platinol® and Platinol®-AQ); Chlorambusyl (also known as Lukelan®); Cyclophosphamide (Citoxane® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosphamide (Ifex®); Prednumustine Procarbazine (Matulane®); Mechloretamine (nitrogen mustard, mustin and mechloroethamine hydrochloride, also known as Mustargen®); Streptosocin (Zanosah®); Thiotepa (thiophosphoamide, TESPA and TSPA, Thioplex) Also known as Cyclophosphamide); cyclophosphamide (Endoxan®, Citoxane®, Neosar®, Procitox®, Revimmune®); and Bendamustine HCl (Treanda (Treanda) Includes, but is not limited to, registered trademarks)).

Examples of anthracyclines include, for example, doxorubicin (Adriamycin® and Rubex®); bleomycin (lenoxane®); daunorubicin (daunorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, Cerubidine®); daunorubicin. Liploids (Daunorubicin citrate liposomes, DaunoXome®); Mitoxantron (DHAD, Novantron®); Epirubicin (Ellence ^TM ); Idalbisin (Idamicin®, Idamycin PFS®); Mightomycin C (Mutamycin®); geldanamycin; harbimycin; ravidomycin; and desacetyl ravidomycin.

Combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecules alone or in combination with other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecules) and the compounds in Table 1). Examples of vinca alkaloids that can be used in combination with are vinorelbine bintaltrate (navelbine®), vincristine (oncovin®) and vindesine (Eldisine®); vinblastine (vinblastine sulfate, vinca leukoblastin and Also known as VLB, Alkaban-AQ® and Velban®; and vinorelbine (navelbine®), but not limited to these.

Combination therapy disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecule alone or in combination with other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) and compounds in Table 1). Examples of proteosome inhibitors that can be used in combination with are voltezomib (Velcade®); calfilzomib (PX-171-007, (S) -4-methyl-N-((S) -1-(((S) -1-((S). ) -4-Methyl-1-((R) -2-methyloxylan-2-yl) -1-oxopentann-2-yl) amino) -1-oxo-3-phenylpropane-2-yl) -2 -((S) -2- (2-morpholinoacetamide) -4-phenylbutaneamide) -pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770); O -Methyl-N- [(2-Methyl-5-thiazolyl) carbonyl] -L-ceryl-O-methyl-N-[(1S) -2-[(2R) -2-methyl-2-oxylanyl] -2 -Oxo-1- (phenylmethyl) ethyl] -L-serine amide (ONX-0912); Danoprevir (RG7227, CAS 850876-88-9); Ixazomib (MLN2238, CAS 1072833-77-2); and (S)- Includes, but is not limited to, N-[(phenylmethoxy) carbonyl] -L-leucyl-N- (1-formyl-3-methylbutyl) -L-leucine amide (MG-132, CAS 133407-82-6). ..

In certain embodiments, the combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecule alone or other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) and the compounds of Table 1). In combination with a tyrosine kinase inhibitor (eg, a receptor tyrosine kinase (RTK) inhibitor). Examples of tyrosine kinase inhibitors are epithelial cell growth factor (EGF) pathway inhibitors (eg, epithelial cell growth factor receptor (EGFR) inhibitors), vascular endothelial growth factor (VEGF) pathway inhibitors (eg, vascular endothelial). Cell growth factor receptor (VEGFR) inhibitors (eg, VEGFR-1 inhibitors, VEGFR-2 inhibitors, VEGFR-3 inhibitors)), platelet-derived growth factor (PDGF) pathway inhibitors (eg, platelet-derived growth factors) Includes, but is not limited to, receptor (PDGFR) inhibitors (eg, PDGFR-β inhibitors), RAF-1 inhibitors, KIT inhibitors and RET inhibitors. In certain embodiments, the anticancer agents used in combination with the hedgehog inhibitor are axitinib (AG013736), bostinib (SKI-606), sedilanib (RECENTIN ^TM , AZD2171), dasatinib (SPRYCEL®, BMS-354825), ellotinib. (Tarceva®), Gefitinib (Iressa®), Imatinib (Gleevec®, CGP57148B, STI-571), Lapatinib (Tykerb®, TYVERB®), Restaurtinib (CEP) -701), Neratinib (HKI-272), Nirotinib (Tasigna®), Semaxanib (Semaxinib, SU5416), Sunitinib (Sutent®, SU11248), Toceranib (Paradia®), Bandetanib (ZACTIMA) (Registered Trademarks), ZD6474), Bataranib (PTK787, PTK / ZK), Trustuzumab (Herceptin®), Bebasizumab (Avastin®), Ritziximab (Ritzanib®), Setuximab (Arbitax®) )), Panitummab (Vectibix®), Lanibizumab (Lucentis®), Sunitinib (Tasigna®), Sorafenib (Nexavar®), Alemtuzumab (Campus®), Gemtuzumab ozogamicin (Myrotarg®), ENMD-2076, PCI-32765, AC220, lactated dobitinib (TKI258, CHIR-258), BIBW 2992 (TOVOK ^TM ), SGX523, PF-04217903, PF- 02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tibozanib (AV- 951), OSI-930, MM-121, XL-184, XL-647, XL228, AEE788, AG-490, AST-6, BMS-599626, CUDC-101, PD153035, peritinib (EKB-569), bandetanib ( zactima), WZ3146, WZ4002, WZ8040, ABT-869 Nifanib), AEE788, AP24534 (ponatinib), AV-951 (tibozanib), hydrochloric acid, BAY 73-4506 (regorafenib), brivanib alaninate (BMS-582664), brivanib (BMS-540215), sedilanib (AZD2171), CHIR -258 (dovitinib), CP 673451, CYC116, E7080, Ki8751, macitinib (AB1010), MGCD-265, motesanib diphosphate (AMG-706), MP-470, OSI-930, pazopanib hydrochloride, PD173074, tosilic acid It is selected from the group consisting of sorafenib (Bay 43-9006), SU 5402, TSU-68 (SU6668), batalanib, XL880 (GSK1363089, EXEL-2880). Further examples of hedgehog inhibitors are Bismodegib (2-chloro-N- [4-chloro-3- (2-pyridinyl) phenyl] -4- (methylsulfonyl) -benzamide, GDC-0449, PCT Publication WO 06/028958. ); 1- (4-Chloro-3- (trifluoromethyl) phenyl) -3-((3- (4-fluorophenyl) -3,4-dihydro-4-oxo-2-quinazolinyl) methyl) ) -Urea (CAS 330796-24-2); N-[(2S, 3R, 3'R, 3aS, 4'aR, 6S, 6'aR, 6'bS, 7aR, 12'aS, 12'bS) -2', 3', 3a, 4,4', 4'a, 5,5', 6,6', 6'a, 6'b, 7,7', 7a, 8', 10', 12 ', 12'a, 12'b-Eikosahydro-3,6,11', 12'b-Tetramethylspiro [Flo [3,2-b] pyridine-2 (3H), 9'(1'H)- Naft [2,1-a] azulene] -3'-yl] -methanesulfonamide (IPI926, CAS 1037210-93-7); and 4-fluoro-N-methyl-N- [1- [4- (1) -Methyl-1H-pyrazole-5-yl) -1-phthalazinyl] -4-piperidinyl] -2- (trifluoromethyl) -benzamide (LY2940680, CAS 1258861-20-9); , Not limited to these. Selective tyrosine kinase inhibitors are sunitinib, erlotinib, gefitinib; or sorafenib erlotinib hydrochloride (Tarceva®); linifanib (N- [4- (3-amino-1H-indazole-4-yl) phenyl] -N. '-(2-Fluoro-5-methylphenyl) urea, also described as ABT 869, also available from Genentech); Sunitinib malate (Sutent®); Bostinib (4-[(2,4-dichloro-5) -Methoxyphenyl) amino] -6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy] quinoline-3-carbonitrile, also known as SKI-606, US patent 6,780,996 ); Dasatinib (Sprycel®); Pazopanib (Votrient®); Sorafenib (Nexavar®); zactima (ZD6474); and imatinib or imatinib mesylate (Gilvec®) And Gleevec®.

In certain embodiments, the combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecule alone or other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) and the compounds of Table 1). (In combination with) is bevasizumab (Avastin®), oxytinib (Inwriter®); brivanib araninate (BMS-582664, (S)-((R) -1- (4- (4- (4- (4-) Fluoro-2-methyl-1H-Indol-5-yloxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazine-6-yloxy) Propane-2-yl) 2-aminopropanol ); Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®); Sedilanib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS 928326) -83-4); Foretinib (GSK1363089); Terratinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319-70-8); tibozanib (AV951, CAS 475108-18-0); legorafenib (BAY73-4506, CAS 755037-03-7); batalanib dihydrogenoxide (PTK787, CAS 212141-51-0); brivanib (PTK787, CAS 212141-51-0) BMS-540215, CAS 649735-46-6); Bandetanib (Caprelsa® or AZD6474); Motesanib diphosphate (AMG706, CAS 857876-30-3, N- (2,3-dihydro-3,3) -Dimethyl-1H-Indol-6-yl) -2-[(4-pyridinylmethyl) amino] -3-pyridinecarboxamide, described in PCT Publication WO 02/06647); dovitinib dilactic acid (TKI258, CAS 852433-84-2). ); Linifanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS 849217-68-1); Restaurtinib (CAS 111358-88-4); N- [5-[[[5- (1,1) -Dimethylethyl) -2-oxazolyl] methyl] thio] -2-thiazolyl] -4-piperidi Ncarboxamide (BMS38703, CAS 345627-80-7); (3R, 4R) -4-amino-1-((4-((3-methoxyphenyl) amino) pyrrolo [2,1-f] [1,2 , 4] Triazine-5-yl) Methyl) piperidine-3-ol (BMS690514); N- (3,4-dichloro-2-fluorophenyl) -6-methoxy-7-[[(3aα, 5β, 6aα) -Octahydro-2-methylcyclopenta [c] pyrrole-5-yl] methoxy] -4-quinazolineamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-( 3-Pyridinyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] amino] -N- [3- (trifluoromethyl) phenyl] -benzamide (BHG712, CAS 940310-85-0); and Combined with vascular endothelial cell proliferation factor (VEGF) receptor inhibitors, including, but not limited to, Afribelcept (Eylea®).

An example of an anti-VEGF antibody is a monoclonal antibody that binds to the same epitope as the monoclonal anti-VEGF antibody A4.6.1 produced by the hybridoma ATCC HB 10709; produced by Presta et al. (1997) Cancer Res. 57: 4593-4599. Includes, but is not limited to, recombinant humanized anti-VEGF monoclonal antibodies. In some embodiments, the anti-VEGF antibody is bevacizumab (BV), also known as rhumab VEGF or Avastin®. It contains mutant human IgGl framework regions and antigen binding complementarity determining regions from the mouse anti-hVEGF monoclonal antibody A.4.6.1, which block the binding of human VEGF to its receptor. Bevacizumab and other humanized anti-VEGF antibodies are further described in US Pat. No. 6,884,879, published February 26, 2005. Further antibodies include G6 or B20 series antibodies (eg, G6-31, B20-4.1) as disclosed in PCT Publication WO 2005/012359, PCT Publication WO 2005/044853, and the content of these patent applications. , Incorporated herein by reference. For additional antibodies, U.S. Pat. Nos. 7,060,269, 6,582,959, 6,703,020, 6,054,297, W098 / 45332, WO96 / 30046, WO94 / 10202, EP0666868B1 See U.S. Patent Application Publication No. 200609360, No. 200609360, No. 20050186208, No. 20030206899, No. 20030190317, No. 20030203409 and No. 200501112126; and Popkov et al, Journal of Immunological Methods 288: 149-164 (2004). Other antibodies include residues F17, Ml 8, D19, Y21, Y25, Q89, 191, Kl 01, El 03 and C104, or contain residues F17, Y21, Q22, Y25, D63, 183 and Q89. Includes those that bind to the functional epitope of human VEGF.

In certain embodiments, the combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecule alone or other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) and compounds in Table 1). In combination with) is combined with a PI3K inhibitor. In some embodiments, the PI3K inhibitor is an inhibitor of PI3K delta and gamma isoforms. Examples of PI3K inhibitors that can be used in combination are disclosed, for example, in WO2010 / 036380, WO2010 / 006086, WO09 / 114870, WO05 / 11556 and GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL-101, CAL 263, SF1126, PX-886 and dual PI3K inhibitors (eg Novartis BEZ 235). Further examples of PI3K inhibitors are 4- [2- (1H-indazole-4-yl) -6-[[4- (methylsulfonyl) piperazin-1-yl] methyl] thieno [3,2-d] pyrimidin. -4-Il] Morphorin (also known as GDC 0941, described in PCT Publications WO09 / 036082 and WO09 / 055730); 2-Methyl-2- [4- [3-Methyl-2-oxo-8- (Kinoline) -3-yl) -2,3-dihydroimidazo [4,5-c] quinoline-1-yl] phenyl] propionitrile (also known as BEZ 235 or NVP-BEZ 235, described in PCT Publication WO 06/122806) 4- (Trifluoromethyl) -5- (2,6-dimorpholinopyrimidine-4-yl) pyridine-2-amine (also known as BKM120 or NVP-BKM120, described in PCT Publication WO 2007/084766); Tozacertibu ( VX680 or MK-0457, CAS 639089-54-6); (5Z) -5-[[4- (4-pyridinyl) -6-quinolinyl] methylene] -2,4-thiazolidinedione (GSK1059615, CAS 958852-01) -2); (1E, 4S, 4aR, 5R, 6aS, 9aR) -5- (acetyloxy) -1-[(di-2-propenylamino) methylene] -4,4a, 5,6,6a, 8 , 9,9a-Octahydro-11-Hydroxy-4- (methoxymethyl) -4a,6a-dimethyl-cyclopenta [5,6] naphtho [1,2-c] pyran-2,7,10 (1H) -trion (PX866, CAS 502632-66-8); 8-phenyl-2- (morpholin-4-yl) -chromen-4-one (LY294002, CAS 154447-36-6); 2-amino-8-ethyl-4 -Methyl-6- (1H-pyrazole-5-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one (SAR 245409 or XL 765); 1,3-dihydro-8- (6-methoxy) -3-Pyridinyl) -3-Methyl-1- [4- (1-piperazinyl) -3- (trifluoromethyl) phenyl] -2H-imidazole [4,5-c] quinoline-2-one ,, (2Z ) -2-Butendioate (1: 1) (BGT 226); 5-Fluoro-3-phenyl-2-[(1S) -1- (9H-Prin-6-ylamino) ethyl] -4 (3H) -Kinazolinone (CAL101) 2-Amino-N- [3- [N- [3-[(2-Chloro-5-methoxyphenyl) amino] quinoxalin-2-yl] sulfamoyl] phenyl] -2-methylpropanamide (SAR 245408 or XL) 147); and (S) -pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5- [2- (2,2,2-trifluoro-1,1-dimethyl-ethyl)) -Penyl-4-yl] -thiazole-2-yl} -amide) (BYL719), but not limited to these.

In certain embodiments, the combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecules alone or other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecules) and the compounds of Table 1). In combination with) are mTOR inhibitors such as rapamycin, everolimus (Torisel®), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE. -354, Palomid 529 (P529), PF-04691502 or PKI-587, Lidaforolimus (formerly known as everolimus, (1R, 2R, 4S) -4-[(2R) -2-[(1R, 9S) , 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28Z, 30S, 32S, 35R) -1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29, 35-Hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo [30.3.1.0 ^4,9 ] Hexatria Conta-16,24,26,28- Tetraen-12-yl] propyl] -2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, described in PCT Publication WO 03/064383); everolimus (Affinitol® or RAD001); rapamycin (AY22989,). Sirolimus®); Semapimod (CAS 164301-51-3); Everolimus, (5- {2,4-bis [(3S) -3-methylmorpholin-4-yl] pyrido [2,3-d] ] Pyrimidine-7-yl} -2-methoxyphenyl) methanol (AZD8055); 2-amino-8- [trans-4- (2-hydroxyethoxy) cyclohexyl] -6- (6-methoxy-3-pyridinyl)- 4-Methyl-pyrido [2,3-d] pyrimidin-7 (8H) -on (PF04691502, CAS 1013101-36-4); and N ^2- [1,4-dioxo-4- [[4- (4) -Oxo-8-phenyl-4H-1-benzopyran-2-yl) morpholinium-4-yl] methoxy] butyl] -L-arginylglycyl-L-α-aspartyl L-serine-, intramolecular salt (SF1) 126, CAS 936487-67-1), (1r, 4r) -4- (4-amino-5- (7-methoxy-1H-indole-2-yl) imidazo [1,5-f] [1,2 , 4] Triazine-7-yl) cyclohexanecarboxylic acid (OSI-027); and combined with one or more mTOR inhibitors selected from one or more of XL765.

In certain embodiments, the combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecule alone or other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) and the compounds of Table 1). In combination with BRAF inhibitors, such as GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720 and sorafenib tosylate (Bay 43-9006). In a further embodiment, the BRAF inhibitor is legorafenib (BAY73-4506, CAS 755037-03-7); tibozanib (AV951, CAS 475108-18-0); vemurafenib (Zelboraf®, PLX-4032, CAS 918504-). 65-1); Encorafenib (also known as LGX818); 1-methyl-5-[[2- [5- (trifluoromethyl) -1H-imidazol-2-yl] -4-pyridinyl] oxy] -N -[4- (Trifluoromethyl) phenyl-1H-benzimidazol-2-amine (RAF265, CAS 927880-90-8); 5- [1- (2-hydroxyethyl) -3- (pyridin-4-yl) ) -1H-Pyrazole-4-yl] -2,3-dihydroinden-1-one oxime (GDC-0879, CAS 905281-76-7); 5- [2- [4- [2- (dimethylamino) ethoxy) ] Phenyl] -5- (4-pyridinyl) -1H-imidazole-4-yl] -2,3-dihydro-1H-inden-1-onoxime (GSK2118436 or SB590885); (+/-)-methyl (5-) (2- (5-Chloro-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole-1-yl) -1H-benzimidazole-2-yl) Carbamate (XL) -281 and also known as BMS908662) and N- (3- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) propan-1-sulfonamide Includes, but is not limited to, (also known as PLX4720).

In certain embodiments, the combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecule alone or other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) and compounds in Table 1). In combination with) is combined with a MEK inhibitor. In some embodiments, a combination of anti-PD-1 antibody and MEK inhibitor is used to treat a cancer (eg, a cancer described herein). In some embodiments, the cancer treated in combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematopoietic tumor or renal cell carcinoma. In some embodiments, the cancer comprises a BRAF mutation (eg, BRAF V600E mutation), BRAF wild type, KRAS wild type or activated KRAS mutation. Cancer can be early, middle or late. Sermethinib (5-[(4-bromo-2-chlorophenyl) amino] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-benzoimidazole-6-carboxamide, also known as AZD6244 or ARRY 142886 ); ARRY-142886 tramethinib dimethylsulfoxide (GSK-1120212, CAS 1204531-25-80); G02442104 (also known as GSK1120212), RDEA436; N- [3,4-difluoro- 2-[(2-Fluoro-4-iodophenyl) amino] -6-methoxyphenyl] -1-[(2R) -2,3-dihydroxypropyl] -cyclopropanesulfonamide (also known as RDEA119 or BAY869766, PCT Publication No. WO20070140111); RDEA119 / BAY 869766, AS703026; G00039805 (also known as AZD-6244 or selumetinib), BIX 02188; BIX 02189; 2-[(2-Chloro-4-iodophenyl) amino]- N- (Cyclopropylmethoxy) -3,4-difluoro-benzamide (also known as CI-1040 or PD184352, described in PCT Publication WO2000035436); CI-1040 (PD-184352), N-[(2R)- 2,3-Dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] -benzamide (also known as PD0325901, described in PCT Publication WO2002006213); PD03259012'-amino -3'-Methoxyflavon (known as PD98059 available from Biaffin GmbH & Co., KG, Germany); PD98059, 2,3-bis [amino [(2-aminophenyl) thio] methylene] -butanedinitrile (Also known as U0126, described in US Pat. No. 2,779,780); U0126, XL-518 (also known as GDC-0973, CasNo. 1029872-29-4, available from ACC Corp.); GDC- 0973 (Methoxyone, [3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] phenyl] [3-hydroxy-3- (25) -2-piperidinyl-l-a Zetizinyl]-), G-38963; and G02443714 (also known as AS703206) or any pharmaceutically acceptable salt or solvate thereof, including, but not limited to, any MEK inhibitor can be used in combination. Examples of additional MEK inhibitors are disclosed in WO2013 / 019906, WO03 / 077914, WO2005 / 121142, WO2007 / 04415, WO2008 / 024725 and WO2009 / 085983, the contents of which are described herein by reference. Include in the book. Further examples of MEK inhibitors are vinimethinib (6- (4-bromo-2-fluorophenylamino) -7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy) -amide, Also known as MEK162, CAS 1073666-70-2, described in PCT Publication WO200307794); 2,3-bis [amino [(2-aminophenyl) thio] methylene] -butanedinitrile (also known as U0126, US Pat. No. 2,779,780); (3S, 4R, 5Z, 8S, 9S, 11E) -14 (ethylamino) -8,9,16-trihydroxy-3,4-dimethyl-3, 4,9,19-Tetrahydro-1H-2-benzoxacyclotetradecine-1,7 (8H) -dione] (also known as E6201 and described in PCT Publication WO2003076424); Bemuraphenib (PLX-4032, CAS 918504) -65-1); (R) -3- (2,3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine -4,7 (3H, 8H) -dione (TAK-733, CAS 1035555-63-5); pimacertibu (AS-703026, CAS 1204531-26-9); 2- (2-fluoro-4-iodophenylamino) ) -N- (2-Hydroxyethoxy) -1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4-difluoro-2-[(2-fluoro- 4-Iodophenyl) Amino] -N- (2-Hydroxyethoxy) -5-[(3-oxo- [1,2] Oxazinean-2-yl) Methyl] benzamide (CH 4987655 or Ro 4987655) , Not limited to these.

In certain embodiments, the combination therapies disclosed herein (eg, anti-PD-1 or PD-L1 antibody molecule alone or other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) and compounds in Table 1). In combination with) is combined with JAK2 inhibitors such as CEP-701, INCB18424, CP-690550 (tasocitinib). Examples of JAK inhibitors are ruxolitinib (Jakafi®); tofacitinib (CP690550); axitinib (AG013736, CAS 319460-85-0); 5-chloro-N2-[(1S) -1- (5-fluoro). -2-Pyrimidinel) ethyl] -N4- (5-Methyl-1H-Pyrazole-3-yl) -l2,4-pyrimidinediamine (AZD1480, CAS 935666-88-9); (9E) -15- [2- (1-pyrrolidinyl) ethoxy] -7,12,26-trioxa-19,21,24-triazatetracyclo [18.3.1.12,5.114,18] -hexacosa-1 (24), 2 , 4,9,14,16,18 (25), 20,22-Nonaen (SB-1578, CAS 937273-04-6); Momelotinib (CYT 387); Varicitinib (INCB-028050 or LY-3009104); Pacritinib (SB1518); (16E) -14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo [19.3.1.12,6.18,12] heptacosa-1 (25), 2,4,6 (27), 8,10,12 (26), 16,21,23-decaen (SB 1317); gandotinib (LY 2784544); and N, N-dicyclopropyl-4-[(1) , 5-dimethyl-1H-pyrazole-3-yl) amino] -6-ethyl-1,6-dihydro-1-methyl-imidazole [4,5-d] pyrrolo [2,3-b] pyridin-7- Includes, but is not limited to, carboxamide (BMS 911543).

In certain embodiments, the combination therapies disclosed herein include paclitaxel or a paclitaxel agent, such as taxol®, protein-binding paclitaxel (eg, abraxane®). Examples of paclitaxel agents are nanoparticle albumin-bound paclitaxel (Abraxane, sold by Abraxis Bioscience), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin, sold by Protarga), polyglutamate-bound paclitaxel (PG-paclitaxel, paclitaxel, polygourmet). CT-2103, XYOTAX, Cell Therapeutic), Tumor Activation Prodrug (TAP), ANG105 (Angiopep-2 bound to 3 paclitaxel molecules, sold by ImmunoGen), Paclitaxel-EC-1 (erbB2 recognition peptide EC-1) Paclitaxel bound to; Li et al., Biopolymers (2007) 87: 225-230) and glucose-conjugated paclitaxel (eg, 2'-paclitaxel methyl 2-glucopyranosyl succinate, Liu et al., Bioorganic) & Medicinal Chemistry Letters (2007) 17: 617-620), but not limited to these.

In some embodiments, an anti-PD-1 or PD-L1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3 or anti-TIM-3 antibody molecule), is a killer cell immunoglobulin-like receptor. It is administered in combination with an antibody against (here also referred to as "anti-KIR antibody"). In certain embodiments, the combination of anti-PD-1 antibody molecule and anti-KIR antibody described herein can be used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor, eg, an advanced solid tumor). Treat.

In some embodiments, anti-PD-1 or PD-L1 antibody molecules are combined with cell-mediated immunotherapy (eg, anti-LAG-3 or anti-TIM-3 antibody molecules) alone or in combination with other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecules). Administer in combination with Provenge (eg, Sipuleucel) and optionally cyclophosphamide. In some embodiments, a combination of anti-PD-1 antibody molecule, provenge and / or cyclophosphamide is used to cancer, eg, cancer as described herein (eg, prostate cancer, eg, advanced prostate cancer). To treat.

In other embodiments, the anti-PD-1 or PD-L1 antibody molecule, alone or in combination with another immunomodulator (eg, anti-LAG-3 or anti-TIM-3 antibody molecule), is a vaccine, eg, dendritic. Administer in combination with the cellular kidney cancer (DC-RCC) vaccine. In some embodiments, the combination of an anti-PD-1 antibody molecule and a DC-RCC vaccine is used to cancer, eg, cancer as described herein (eg, kidney cancer, eg, metastatic renal cell carcinoma (RCC) or clear). Treat Cell Renal Cell Carcinoma (CCRCC)).

In yet another embodiment, the anti-PD-1 or PD-L1 antibody molecule is used alone or in combination with another immunomodulator (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) for chemotherapy and / or Administer in combination with immunotherapy. For example, using an anti-PD-1 or PD-L1 antibody molecule, alone or with chemotherapy or other anti-cancer agents (eg, salidamide analogs, eg, renalide midide), anti-TIM-3 antibodies, tumor antigen pulse trees. Myeloma is treated in combination with one or more of the fusion of dendritic cells, tumor cells and dendritic cells (eg, electrical fusion) or vaccination with immunoglobulin idiotypes produced by malignant plasma cells. In some embodiments, an anti-PD-1 or PD-L1 antibody molecule is used in combination with an anti-TIM-3 antibody to treat myeloma, such as multiple myeloma.

In certain embodiments, the anti-PD-1 or PD-L1 antibody molecule is used alone or in combination with other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) in combination with chemotherapy. And treat lung cancer, eg, non-small cell lung cancer. In some embodiments, the anti-PD-1 or PD-L1 antibody molecule is combined with platinum doublet therapy for the treatment of lung cancer.

In yet another embodiment, the anti-PD-1 or PD-L1 antibody molecule is used alone or in combination with other immunomodulators (eg, anti-LAG-3 or anti-TIM-3 antibody molecule) for renal cancer. For example, treating renal cell carcinoma (RCC) (eg, clear cell renal cell carcinoma (CCRCC) or metastatic RCC. Anti-PD-1 or PD-L1 antibody molecule, immune-based strategy (eg, interleukin-2 or Interferon-α), targeting agents (eg, VEGF inhibitors such as monoclonal antibodies to VEGF); VEGF tyrosine kinase inhibitors such as snitinib, sorafenib, axitinib and pazopanib; RNAi inhibitors) or downstream of VEGF signaling It can be administered in combination with a mediator inhibitor, eg, a mammalian target (mTOR) inhibitor of rapamycin, eg, one or more of everolimus and temsirolimus.

Examples of suitable treatments to be used in combination for the treatment of pancreatic cancer are chemotherapeutic agents such as paclitaxel or paclitaxel (eg, taxols, albumin-stabilized nanoparticles paclitaxel formulations (eg, abraxane) or liposome paclitaxel formulations. Paclitaxel preparations such as); gemcitabine (eg, gemcitabine alone or in combination with AXP107-11); oxaliplatin, 5-fluorouracil, capecitabin, rubitecan, epirubicin hydrochloride, NC-6004, cisplatin, docetaxel (eg, taxotere), mitomycin C , Other chemotherapeutic agents such as iphosphamide; interferon; tyrosine kinase inhibitors (eg, EGFR inhibitors (eg, erlotinib, paclitaxel, setuximab, nimotzumab); HER2 / neu receptor inhibitors (eg, trussutzumab); dual kinases Inhibitors (eg, bostinib, salacatinib, rapatinib, bandetanib); multikinase inhibitors (eg, sorafenib, snitinib, XL184, paclitaxel); VEGF inhibitors (eg, bevasizumab, AV-951, brivanib); , XR303); Cancer vaccines (eg, GVAX, surviving peptides); COX-2 inhibitors (eg, celecoxib); IGF-1 receptor inhibitors (eg, AMG 479, MK-0646); mTOR inhibitors (eg, eg. Everolimus, temsirolimus); IL-6 inhibitors (eg, CNTO 328); cyclin-dependent kinase inhibitors (eg, P276-00, UCN-01); modified energy metabolism-oriented (AEMD) compounds (eg, CPI-). 613); HDAC inhibitor (eg, bolinostat); TRAIL receptor 2 (TR-2) agonist (eg, konatumumab); MEK inhibitor (eg, AS703026, selmethinib, GSK1120212); Raf / MEK dual kinase inhibitor (eg) , RO5126766); Notch signal transduction inhibitor (eg, MK0752); Monochromic antibody-antibody fusion protein (eg, L19IL2); Curcumin; HSP90 inhibitor (eg, Tanespimycin, STA-9090); rIL-2 ;, Deni Leukindiftitox; topoisomerase 1 inhibitor (eg, irinotecan, PEP02); statin (eg, simvastatin); factor VIIa inhibitor (eg PCI-27483); AKT inhibitor (eg RX-0201); hypoxicosis activating prodrug (eg TH-302); metformin hydrochloride, gamma-secretase inhibitor (eg RO4929097) Ribonucleotide reductase inhibitors (eg 3-AP); immunotoxins (eg HuC242-DM4); PARP inhibitors (eg KU-0059436, veriparib); CTLA-4 inhibitors (eg CP-675,206, ipilimumab) ); AdV-tk treatment; proteasome inhibitors (eg, voltezomib (Velcade), NPI-0052); thiazolidinedione (eg, pioglycazone); NPC-1C; aurora kinase inhibitors (eg, R763 / AS703569), CTGF inhibitors (Eg, FG-3019); siG12D LODER; and radiotherapy (eg, tomotherapy, stereotactic radiation, proton therapy), surgery and combinations thereof, but not limited to these. In certain embodiments, a combination of paclitaxel or a paclitaxel agent with gemcitabine can be used with the anti-PD-1 antibody molecule described herein.

Examples of suitable treatments to be used in combination for the treatment of small cell lung cancer are chemotherapeutic agents such as etopocid, carboplatin, cisplatin, irinotecan, topotecan, gemcitabine, liposome SN-38, bendamstin, temozoromide, verotecan, NK012, FR901228, flavopyridol); tyrosine kinase inhibitors (eg, EGFR inhibitors (eg, erlotinib, gefitinib, setuximab, panitumumab); multikinase inhibitors (eg, sorafenib, snitinib); VEGF inhibitors (eg, bebasizumab, bandetanib) ); Cancer vaccines (eg, GVAX); Bcl-2 inhibitors (eg, oblimersen sodium, ABT-263); Proteasome inhibitors (eg, voltezomib (Velcade), NPI-0052), paclitaxel or paclitaxel; docetaxel; IGF-1 receptor inhibitor (eg, AMG 479); HGF / SF inhibitor (eg, AMG 102, MK-0646); chlorokin; aurora kinase inhibitor (eg, MLN8237); radioimmunotherapy (eg, TF2) HSP90 inhibitors (eg, tanespimycin, STA-9090); mTOR inhibitors (eg, everolims); Ep-CAM- / CD3-bispecific antibodies (eg, MT110); CK-2 inhibitors (eg, eg) CX-4945); HDAC inhibitors (eg, verinostats); SMO antagonists (eg, BMS 833923); peptide cancer vaccines and radiotherapy (eg, intensity-controlled radiotherapy (IMRT), fractionated radiotherapy, hypoxic-guided radiotherapy) Therapy), surgery and combinations thereof.

Examples of suitable treatments for use in a combination of treatments for non-small cell lung cancer are chemotherapeutic agents such as binorelvin, cistuximab, docetaxel, pemetrexedodisodium, etopocid, gemcitabine, carboplatin, liposomes SN-38, TLK286, Temozolomid, topotecan, pemetrexedodisodium, azacitidine, irinotecan, tegafur-gimelacyl-oteracil potassium, sapacitabine; tyrosine kinase inhibitors (eg, EGFR inhibitors (eg, errotinib, gefitinib, cetuximab, panitumumab, PF-0029) Nimotuzumab, RO5083945), MET inhibitors (eg, PF-02341066, ARQ 197), PI3K kinase inhibitors (eg XL147, GDC-0941), Raf / MEK dual kinase inhibitors (eg RO5126766), PI3K / mTOR dual Kinase inhibitors (eg XL765), SRC inhibitors (eg dasatinib), dual inhibitors (eg BIBW 2992, GSK1363089, ZD6474, AZD0530, AG-013736, rapatinib, MEHD7945A, linifanib), multikinase inhibitors (eg linifanib) , Soraphenib, snitinib, pazopanib, AMG 706, XL184, MGCD265, BMS-690514, R935788), VEGF inhibitors (eg endostar, endostatin, bebasizumab, cetuximab, BIBF 1120, axitinib, tibozanib, AZD2171), cancer vaccines, eg , BLP25 liposome vaccine, GVAX, recombinant DNA and adenovirus expressing L523S protein), Bcl-2 inhibitors (eg, oblimersen sodium), proteasome inhibitors (eg, voltezomib, calfilzomib, NPI-0052, MLN9708), paclitaxel Or paclitaxel agents, docetaxels, IGF-1 receptor inhibitors (eg, cetuximab, MK-0646, OSI 906, CP-751,871, BIIB022), hydroxychlorokins, HSP90 inhibitors (eg, tanespymycin, STA-9090, AUY922). , XL888), mTOR inhibitors (eg, everolimus, temsirolimus, lidaphorolimus), Ep-CAM- / CD3-bispecific antibodies (eg, e. , MT110), CK-2 inhibitors (eg CX-4945), HDAC inhibitors (eg MS 275, LBH589, bolinostat, valproic acid, FR901228), DHFR inhibitors (eg Pralatrexate), retinoids (eg Pralatrexate) , Bexarotene, tretinone), antibody-drug conjugates (eg SGN-15), bisphosphonates (eg zoledronic acid), cancer vaccines (eg Veragenpmatsucel-L), low molecular weight heparin (LMWH) (eg LMWH) Chinzaparin, Enoxaparin), GSK1572932A, Melatonin, Talactoferrin, Dimesna, Topoisomerase inhibitors (eg, amrubicin, etopocid, carenitecin), Nerphinavir, sirengitide, ErbB3 inhibitors (eg, MM-121, U3-1287), Survivin inhibitors For example, YM155, LY2181308), elibrine mesylate, COX-2 inhibitor (eg, selecoxib), pegfilgrastim, polo-like kinase 1 inhibitor (eg BI 6727), TRAIL receptor 2 (TR-2) agonist. (Eg CS-1008), CNGRC peptide-TNF alpha conjugate, dichloroacetate (DCA), HGF inhibitor (eg SCH 900105), SAR240550, PPAR-gamma agonist (eg CS-7017), gamma-secretase inhibition Agents (eg RO4929097), epi gene therapy (eg 5-azacitidine), nitroglycerin, MEK inhibitors (eg AZD6244), cyclin-dependent kinase inhibitors (eg UCN-01), cholesterol-Fus1, antitubes Phosphorus (eg E7389), Farnesyl-OH-transferase inhibitor (eg Lonafarnib), Immunotoxins (eg BB-10901, SS1 (dsFv) PE38), Fondaparinux, Vascular disruptors (eg AVE8062), PD-L1 inhibitors (eg MDX-1105, MDX-1106), beta-glucans, NGR-hTNF, EMD 521873, MEK inhibitors (eg GSK1120212), epotiron analogs (eg ixavepyrone), kinesin spindle inhibitors (eg) For example, 4SC-205), telomera-targeting agents (eg, KML-001), P70 pathway inhibitors (eg, LY2584702), AKT blockers. It includes, but is not limited to, harmful agents (eg, MK-2206), angiogenesis inhibitors (eg, lenalidomide), Notch signaling inhibitors (eg, OMP-21M18), radiation therapy, surgery and combinations thereof.

Examples of suitable treatments for use in a combination of treatments for ovarian cancer are chemotherapeutic agents (eg, paclitaxel or paclitaxel; docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin; irinotecan, TLK286, iphosphamide, olaparib, oxali. Platin, merphalan, pemetrexedodisodium, SJG-136, cyclophosphamide, etopocid, decitabin); grelin antagonist (eg, AEZS-130), immunotherapy (eg, APC8024, olegobomab, OPT-821), tyrosine kinase inhibition Agents (eg, EGFR inhibitors (eg, errotinib), dual inhibitors (eg, E7080), multikinase inhibitors (eg, AZD0530, JI-101, sorafenib, snitinib, pazopanib), ON 01910.Na), VEGF inhibition Agents (eg, bevasizumab, BIBF 1120, sedilanib, AZD2171), PDGFR inhibitors (eg, IMC-3G3), paclitaxels, topoisomerase inhibitors (eg, carenitecin, irinotecan), HDAC inhibitors (eg, baroproate, bolinostat), folic acid. Receptor inhibitors (eg, furletszumab), angiopoetin inhibitors (eg, AMG 386), epotiron analogs (eg, ixavepyrone), proteasome inhibitors (eg, calfilzomib), IGF-1 receptor inhibitors (eg, OSI) 906, AMG 479), PARP inhibitors (eg, veriparib, AG014699, iniparib, MK-4827), aurora kinase inhibitors (eg, MLN8237, ENMD-2076), angiogenesis inhibitors (eg, renalidomide), DHFR inhibitors (Eg, pralatrexate), radiotherapeutic agents (eg, Hu3S193), statins (eg, robastatin), topoisomerase 1 inhibitors (eg, NKTR-102), cancer vaccines (eg, p53 synthetic length peptide vaccines, auto-OC- DC vaccines), mTOR inhibitors (eg, temsirolimus, everolims), BCR / ABL inhibitors (eg, imatinib), ET-A receptor antagonists (eg, ZD4054), TRAIL receptor 2 (TR-2) agonists (eg, eg) , CS-1008), HGF / SF inhibitors (eg, AMG 102), EGEN-001, Polo-like Kinner Ze 1 inhibitor (eg BI 6727), gamma-secretase inhibitor (eg RO4929097), Wee-1 inhibitor (eg MK-1775), anti-tubulin agents (eg vinorelbine, E7389), immunotoxins (eg Vinorelbine, E7389) For example, Deniroy kindiftix), SB-485232, vasolytic agents (eg AVE8062), integulin inhibitors (eg EMD 525797), kinesin spindle inhibitors (eg 4SC-205), levrimids, HER2 inhibitors (eg HER2 inhibitors). For example, MGAH22), ErrB3 inhibitors (eg, MM-121), radiotherapy; and combinations thereof, but not limited to these.

Examples of suitable treatments for use in combination of treatments for myeloma are, alone or chemotherapy or other anti-cancer agents (eg, thalidomide analogs, eg, lenalidomide), HSCT (Cook, R. (2008) J. Manag Care Pharm. 14 (7 Suppl): 19-25), Anti-TIM-3 antibody (Hallett, WHD et al. (2011) J of American Society for Blood and Marrow Transplantation 17 (8): 1133-145), Tumor Vaccination with immunoglobulin thalidomide type produced by antigen pulsed dendritic cells, fusion of tumor and dendritic cells (eg, electrical fusion) or malignant plasma cells (Yi, Q. (2009) Cancer J. 15 (6) ): One or more combinations of 502-10 Niregyu).

Examples of suitable treatments for use in a combination of treatments for renal cell carcinoma, eg renal cell carcinoma (RCC) or metastatic RCC. Anti-PD-1 antibody molecules can be used with immune-based strategies (eg, interleukin-2 or interferon-α), targeting agents (eg, VEGF inhibitors such as monoclonal antibodies to VEGF, eg bevacizumab (Rini, B.I. et.). al. (2010) J. Clin. Oncol. 28 (13): 2137-2143)); VEGF tyrosine kinase inhibitors such as snitinib, sorafenib, axitinib and pazopanib (Pal. S.K. et al. (2014) Clin. Advances (Reviewed in Hematology & Oncology 12 (2): 90-99)); RNAi inhibitors) or inhibitors of downstream mediators of VEGF signaling, such as mammalian target (mTOR) inhibitors of rapamycin, such as Eberolimus and Temcilolimus. In combination with one or more of (Hudes, G. et al. (2007) N. Engl. J. Med. 356 (22): 2271-2281, Motzer, R.J. et al. (2008) Lancet 372: 449-456) Can be administered.

Examples of suitable treatments for use in combination with the treatment of chronic myelogenous leukemia (AML) according to the present invention are chemotherapy (eg, citarabin, hydroxyurea, clofarabin, melfaran, thiotepa, fludalabine, busulfan, etoposide, cordisepine). , Pentostatin, capecitabin, azacitidine, cyclophosphamide, cladribine, topotecan), tyrosine kinase inhibitors (eg, BCR / ABL inhibitors (eg, imatinib, nirotinib), ON 01910.Na, dual inhibitors (eg, dasatinib) , Bostinib), multikinase inhibitors (eg DCC-2036, ponatinib, sorafenib, snitinib, RGB-286638), interferon alpha, steroids, apoptosis agents (eg omacetaxin mepesccinato), immunotherapy (eg omacetaxin mepesccinato) Allogeneic CD4 + memory Th1-like T cells / fine particle-bound anti-CD3 / anti-CD28, self-cytogenic killer cells (CIK), AHN-12), drugs targeting CD52 (eg, alemtuzumab), HSP90 inhibitors (eg, tanespi) Mycin, STA-9090, AUY922, XL888), mTOR inhibitors (eg, Eberolimus), SMO antagonists (eg, BMS 833923), ribonucleotide reductase inhibitors (eg, 3-AP), JAK-2 inhibitors (eg, eg) INCB018424), hydroxychlorokin, retinoids (eg, fenretinide), cyclin-dependent kinase inhibitors (eg, UCN-01), HDAC inhibitors (eg, verinostat, bolinostat, JNJ-26481585), PARP inhibitors (eg, veriparib). , MDM2 antagonist (eg RO5045337), Aurora B kinase inhibitor (eg TAK-901), radioimmunotherapy (eg Actinium-225 labeled anti-CD33 antibody HuM195), hedgehog inhibitor (eg PF-04449913), Includes, but is not limited to, STAT3 inhibitors (eg OPB-31121), KB004, cancer vaccines (eg AG858), bone marrow transplants, stem cell transplants, radiotherapy and combinations thereof.

Examples of suitable treatments for use in a combination of treatments for chronic lymphocytic leukemia (CLL) are chemotherapeutic agents (eg, fludalabine, cyclophosphamide, doxorubicin, bincristin, chlorambusyl, bendamstin, chlorambusyl, busulfan, gemcitabine, etc. Melfaran, pentostatin, mitoxanthron, 5-azacitidine, pemetrexedodisodium, tyrosine kinase inhibitors (eg, EGFR inhibitors (eg, erlotinib), BTK inhibitors (eg, PCI-32765), multikinase inhibitors (Eg, MGCD265, RGB-286638), CD-20 targeting agents (eg, rituximab, ofatumumab, RO5072759, LFB-R603), drugs targeting CD52 (eg, alemtuzumab), prednisolone, dalbepoetin alfa, renalide, Bcl- 2 inhibitors (eg, ABT-263), immunotherapy (eg, allogeneic CD4 + memory Th1-like T cells / microbound anti-CD3 / anti-CD28, self-cytozygous killer cells (CIK)), HDAC inhibitors (eg, bolinostats) , Valproic acid, LBH589, JNJ-26481585, AR-42), XIAP inhibitors (eg AEG35156), CD-74 targeting agents (eg Miratuzumab), mTOR inhibitors (eg Everolims), AT-101, immunity Toxins (eg, CAT-8015, anti-Tac (Fv) -PE38 (LMB-2)), CD37 targeting agents (eg, TRU-016), radioimmunotherapy (eg, 131-tocittumomab), hydroxychlorokins, perihocin, SRC inhibitors (eg dasatinib), salidamide, PI3K delta inhibitors (eg CAL-101), retinoids (eg fenretinide), MDM2 antagonists (eg RO5045337), prelixaforms, aurora kinase inhibitors (eg MLN8237, TAK) -901), proteasome inhibitors (eg, voltezomib), CD-19 targeting agents (eg, MEDI-551, MOR208), MEK inhibitors (eg, ABT-348), JAK-2 inhibitors (eg, INCB018424). , Hypoxia activating prodrugs (eg TH-302), paclitaxels or paclitaxel agents, HSP90 inhibitors, AKT inhibitors (eg MK2206), HMG-CoA inhibitors (eg, eg Symbatatin), GNKG186, radiation therapy, bone marrow transplantation, stem cell transplantation and combinations thereof, but not limited to these.

Examples of suitable treatments for use in a combination of treatments for acute lymphocytic leukemia (ALL) are chemotherapeutic agents (eg, prednisolone, dexamesazone, bincristin, asparaginase, daunorbisin, cyclophosphamide, citarabin, etoposide, thioguanine, etc. Mercaptopurine, clofalabin, liposome anamicin, busulfan, etoposide, capesitabin, decitabin, azacitidine, topotecan, temozolomide, tyrosine kinase inhibitors (eg, BCR / ABL inhibitors (eg, imatinib, nirotinib), ON 01910.Na, poly Kinase inhibitors (eg, sorafenib)), CD-20 targeting agents (eg, rituximab), CD52 targeting agents (eg, alemtuzumab), HSP90 inhibitors (eg, STA-9090), mTOR inhibitors (eg, eg). Everolimus, rapamycin), JAK-2 inhibitors (eg INCB018424), HER2 / neu receptor inhibitors (eg trussutzumab), proteasome inhibitors (eg voltezomib), methotrexates, asparaginases, CD-22 targeting agents (eg) , Epiratsumab, Inotzumab), Chemotherapy (eg, Self-Cytokai-Induced Killer Cells (CIK), AHN-12), Brinatumomab, Cycline-Dependent Kinase Inhibitors (eg, UCSN-01), CD45 Targeting Agents (eg, BC8) ), MDM2 antagonist (eg RO5045337), immunotoxin (eg CAT-8015, DT2219ARL), HDAC inhibitor (eg JNJ-26481585), JVRS-100, paclitaxel or paclitaxel agent, STAT3 inhibitor (eg OPB-) 31121), PARP inhibitors (eg, veriparib), EZN-2285, radiotherapy, steroids, bone marrow transplants, stem cell transplants or combinations thereof.

Examples of suitable treatments for use in a combination of treatments for acute myeloid leukemia (AML) are chemotherapeutic agents (eg, citarabine, daunorubicin, idarubicin, clofarabin, decitabine, bossaloxins, azacitidine, clofarabin, ribavirin, CPX-351, Treosulfan, eracitarabine, azacitidine), tyrosine kinase inhibitors (eg, BCR / ABL inhibitors (eg, imatinib, nirotinib), ON 01910.Na, multikinase inhibitors (eg, midstaurin, SU 11248, quizartinib, sorafenib) )), Immunotoxins (eg, gemtuzumab ozogamicin), DT388IL3 fusion proteins, HDAC inhibitors (eg, bolinostat, LBH589), prelixahol, mTOR inhibitors (eg, everolims), SRC inhibitors (eg, dasatinib) ), HSP90 inhibitors (eg, STA-9090), retinoids (eg, bexarotene, aurora kinase inhibitors (eg, BI 811283), JAK-2 inhibitors (eg, INCB018424), polo-like kinase inhibitors (eg, BI). 6727), Senersen, CD45 targeting agent (eg BC8), cyclin-dependent kinase inhibitor (eg UCN-01), MDM2 antagonist (eg RO5045337), mTOR inhibitor (eg Everolimus), LY573636-sodium, Includes, but is not limited to, ZRx-101, MLN4924, renalide, immunotherapy (eg, AHN-12), histamine dihydrogenate, radiation therapy, bone marrow transplantation, stem cell transplantation and combinations thereof.

Examples of suitable treatments for use in a combination of treatments for multiple myeloma (MM) are chemotherapeutic agents (eg, melfaran, amihostin, cyclophosphamide, doxorubicin, clofarabin, bendamstin, fludalabine, adriamycin, SyB). L-0501), salidamide, renalide, dexamesazone, prednison, pomalidemid, proteasome inhibitors (eg, voltezomib, calfilzomib, MLN9708), cancer vaccines (eg, GVAX), CD-40 targeting agents (eg, SGN-40, CHIR). -12.12), perihocin, zoledronic acid, immunotherapy (eg MAGE-A3, NY-ESO-1, HuMax-CD38), HDAC inhibitors (eg bolinostat, LBH589, AR-42), apridin, cyclin-dependent kinase Inhibitors (eg PD-0332991, dynacyclib), arsenic trioxide, CB3304, HSP90 inhibitors (eg KW-2478), tyrosine kinase inhibitors (eg EGFR inhibitors (eg sesximab), polykinase inhibitors (eg) For example, AT9283)), VEGF inhibitor (eg, bevasizumab), prelixaform, MEK inhibitor (eg, AZD6244), IPH2101, atorvastatin, immunotoxin (eg, BB-10901), NPI-0052, radioimmunotherapy (eg, eg, AT9283)). Ittrium Y90 ibritsumomabutiuxetane), STAT3 inhibitor (eg OPB-31121), MLN4924, Aurora kinase inhibitor (eg ENMD-2076), IMGN901, ACE-041, CK-2 inhibitor (eg CX- 4945), including, but not limited to, radiation therapy, bone marrow transplantation, stem cell transplantation and combinations thereof.

Examples of suitable treatments for use in a combination of treatments for prostate cancer are chemotherapeutic agents (eg, docetaxels, carboplatins, fludalabins), avilaterons, hormonal therapies (eg, flutamides, bicartamides, nitamides, ciproterones acetate, ketoconazoles, aminos). Glutetimid, avalerix, degarelix, leuprolide, gocerelin, tryptreline, busererin), tyrosine kinase inhibitors (eg, dual kinase inhibitors (eg, rapatinib), multikinase inhibitors (eg, sorafenib, snitinib)), VEGF inhibitors (Eg, bebasizumab), TAK-700, cancer vaccines (eg BPX-101, PEP223), renalide, TOK-001, IGF-1 receptor inhibitors (eg sixtumumab), TRC105s, Aurora A kinase inhibitors (eg) , MLN8237), proteasome inhibitors (eg voltezomib), OGX-011, radioimmunotherapy (eg HuJ591-GS), HDAC inhibitors (eg valproic acid, SB939, LBH589), hydroxychlorokins, mTOR inhibitors (eg) , Everolimus), lactated dobitinib, diindolylmethane, efavilents, OGX-427, genistine, IMC-3G3, bafetinib, CP-675,206, radiotherapy, surgery or combinations thereof.

Combination therapy, surgery; radiation therapy (eg, external beam therapy, including three-dimensional, equiangular radiation therapy for which the radiation field is designed, local radiation (eg, direct radiation to a planned target or organ) or intensive radiation. ), But can be combined with one or more of the existing modalities for the treatment of cancer, but not limited to these. Intensive radiation is selected from the group consisting of stereotactic radiosurgery, segmented stereotactic radiosurgery and intensity-controlled radiotherapy. Concentrated radiation has a radiation source selected from the group consisting of particle beams (protons), cobalt-60 (photons) and linear accelerators (x-rays), for example as described in WO2012 / 177624. ..

Radiation therapy includes, but is not limited to, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiation therapy, systemic radiation therapy, radiation therapy and continuous or transient interstitial short head therapy. Can be administered by one or a combination of. The term "brachycephaly treatment" refers to radiation therapy delivered from spatially localized radioactive material inserted into or near a tumor or other proliferative tissue disease site. The term refers to the radioisotopes of radioactive isotopes (eg, At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and Lu). ) Is intended to include, but is not limited to, exposure to. Suitable sources of radiation for use as the cellular conditioners of the present invention include both solids and liquids. As a non-limiting example, the radiation source is a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 or a photon, beta particle, gamma radiation as a solid source. Or it can be another radionuclide that emits other lines of treatment. The radioactive material may also be a fluid made from some solution of the radionuclide, eg, a solution of I-125 or I-131, or the radioactive fluid may be a small amount of a solid radionuclide such as Au-198, Y-90. It can be produced using a slurry of a suitable fluid containing particles. In addition, radionuclides can be used in gels or radiomicrospheres.

Nucleic Acids The present invention also relates to nucleic acids comprising heavy and light chain variable regions of antibody molecules and nucleotide sequences encoding CDRs or hypervariable loops, as described herein. The nucleic acid is 3, 6, 15, 30 or 45 with the nucleotide sequence shown herein or a sequence substantially identical thereto (eg, at least about 85%, 90%, 95%, 99% or more identical to it or the sequence listed herein). Contains sequences that do not differ beyond nucleotides).

Vectors Further provided herein are vectors comprising the nucleotide sequences encoding the antibody molecules described herein. In some embodiments, the vector comprises a nucleotide encoding an antibody molecule described herein. In some embodiments, the vector comprises the nucleotide sequences described herein. Vectors include, but are not limited to, viruses, plasmids, cosmids, lambda phage or yeast artificial chromosomes (YACs).

Many vector systems can be used. For example, certain classes of vectors are derived from animal viruses such as bovine papillomavirus, polyomavirus, adenovirus, vaccinia virus, baculovirus, retrovirus (Rous sarcoma virus, MMTV or MOMLV) or SV40 virus. Utilize DNA elements. Other classes of vectors utilize RNA sequences from RNA viruses such as semliki forest virus, eastern equine encephalitis encephalitis virus and flavivirus.

In addition, cells with DNA stably integrated into the chromosome can be selected by introduction of one or more markers that allow selection of gene transfer host cells. Markers can provide, for example, auxotrophic host nutrition, biocide resistance (eg, antibiotics) or resistance to heavy metals such as copper. The selectable marker gene may be directly linked to the expressed DNA sequence or introduced into the same cell by co-transformation. Additional factors may also be required for optimal mRNA synthesis. These elements may include splice signals, as well as transcriptional promoters, enhancers and arrest signals.

Once the expression vector or DNA sequence containing the construct is prepared for expression, the expression vector is gene-introduced or introduced into the appropriate host cell. Achieved this using a variety of techniques such as protoplasmic fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transduction, gene guns, lipid-based gene transfer or other conventional techniques. Can be. For plasma fusion, cells are grown in medium and screened for appropriate activity.

Methods and conditions for culturing the resulting gene-introduced cells and recovering the produced antibody molecules are known to those of skill in the art and can be modified or modified by specific expression vectors and mammalian host cells used as described herein. Can be optimized.

Cells The invention also provides host cells comprising nucleic acids encoding antibody molecules as described herein.

In some embodiments, the host cell has been genetically modified to contain a nucleic acid encoding an antibody molecule.

In some embodiments, the host cell is genetically modified using an expression cassette. The term "expression cassette" refers to a nucleotide sequence, which can affect the expression of a gene in a host compatible with such a sequence. Such cassettes include promoters, open reading frames with or without introns, and stop signals. Additional factors necessary or helpful for expression, for example, inducible promoters, may also be used.

The invention also provides host cells containing the vectors described herein.

The cells can be, but are not limited to, eukaryotic cells, bacterial cells, insect cells or human cells. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.

The following examples illustrate the disclosure and provide certain embodiments, but do not limit the scope of the disclosure.

Example 1: Effect of Targeted Agent on PD-L1 Modulation This Example evaluates the effect of selective therapeutic agents (eg, INC280, MEK162, LGX818 and LDK378) on PD-L1 (CD274) regulation. Selective therapies were evaluated for PD-L1 levels by real-time PCR and flow cytometry. Significant inhibition of PD-L1 by INC280, INC424, MEK162, LGX818 and LDK378 in tumor cells was observed.

INC280 downregulation of PD-L1 protein PD-L1 (CD274) expression was analyzed in cancer cell lines treated with INC280. Cells were obtained from the ATCC and cultured in vitro according to the ATCC instructions. The cell line used was previously characterized by the Cancer Cell Line Encyclopedia Project (www.broadinstitute.org/ccle/home).
Cells seeded on 6-well culture plates were treated with INC280 at various concentrations (10 nM, 100 nM and 1000 nM) for 24 hours, 48 hours and 72 hours. An equal amount of medium (DMSO) was used as a control. Cells were washed with PBS and then harvested using a cell scraper.
For each reaction, 0.5-1 × ¹⁰⁶ cells were stained with 20 μL of anti-human monoclonal PD-L1-PE antibody, clone M1H1 (BD), for 30-60 minutes at 4 ° C. Cells were washed twice and acquired using Canto II with FACSDiva software (BD Bioscience). Data analysis was performed using FlowJo software (Tree Star). Mean fluorescence intensity (MFI) was determined by single cell gating. Unstained cells were used as a gating control.
In vitro treatment of EBC-1 cells (non-small cell lung cancer with cMET amplification (NSCLC)) at INC280 led to marked downregulation of surface expression of PD-L1 as observed by flow cytometry (Fig. 1). The results provided here suggest that INC280 functions as a PD-L1 / PD-1 inhibitor.

INC280, MEK162, INC424, LGX818 and LDK 378 have developed a TaqMan RT PCR assay that downregulates PD-L1 mRNA for the detection of changes in PD-L1 (CD274) expression levels in cell lines and xenograft tumors. .. mRNA was isolated from frozen cell pellet or tumor fragment using the Qiagen RNeasy Mini kit. The isolated RNA was frozen at −80 ° C. RNA quality was confirmed and RNA was quantified using the 2100 Agilent Bioanalyzer according to the Agilent RNA 6000 Nano Kit protocol. cDNA was prepared using the High Capacity RNA-to cDNA Kit (Applied Biosystems).
Real-time PCR reactions were performed in a total volume of 20 μl, including 10 μl Universal PCR master mix (Applied Biosystems), 1 μl human PD-L1 (CD274) probe / primer set (Applied Biosystems) and 8 μl cDNA. Each sample was triplicated. The amount of cDNA produced from 25-50 ng of RNA in the reverse transcription reaction was used in the PCR reaction. Due to the difference in mRNA levels between PD-L1 and GAPDH, two real-time PCR reactions were performed in separate tubes using the same amount of cDNA. Real-time PCR reactions were run in the next program, C1000 Thermal Cycle (BioRad): incubation at 95 ° C for 10 minutes, followed by 40 cycles of 95 ° C for 15 seconds and 60 ° C for 1 minute. After completion of the reaction, PD-L1 average Ct was standardized for each Ct value from the GAPDH control reaction. Each standardized logarithmic value was then converted to a linear value.

Inhibition of PD-L1 expression (mRNA) by INC280 was observed in Hs.746.T tumor (gastric cancer cells with cMET amplification and mutation) xenografts (FIG. 2). Inhibition of PD-L1 mRNA by LDK378 was observed in vitro in H3122 (non-small cell lung cancer with ALK translocation (NSCLC)) (FIG. 3). Downward regulation of PD-L1 mRNA by LGX818 and MEK162 was observed in tumor xenograft models carrying LOXIMV1 (BRAF mutant melanoma, FIG. 4) and HEYA8 (KRAF mutant ovarian cancer, FIG. 5) tumors, respectively. Downward regulation of PD-L1 mRNA by INC424 was observed in a tumor xenograft model carrying UKE-1 (myeloproliferative neoplasm (MPN) strain with JAK2V617F mutation, FIG. 6).
The results provided here show the role of INC280, MEK162, INC424, LGX818 and LDK 378 in the regulation of cancer immune checkpoint molecules. The observed inhibition of PD-L1 expression with these agents indicates that these targeting agents may have immunomodulatory activity in addition to their effect on cancer signaling. Therefore, the results provided herein are that administration of immune checkpoint inhibitor inhibitors such as PD-1, PD-L1, LAG-3 and / or TIM-3 and administration of targeting agents is more potent immunity. Suggests to achieve a reversal of checkpoint-mediated immunosuppression.

Example 2: Effect of LCL161 on immune stimulation This example evaluates the effect of LCL161 on immune stimulation in vitro.
Blood was obtained from a normal healthy donor. Peripheral blood mononuclear cells (PBMCs) were isolated by centrifuging blood in a CPT ^TM tube for 18 minutes at 1800 xg. Cells were washed twice with cold PBS, counted, and then stimulated with 96-well round bottom tissue culture plates (500,000 cells / well) for 5 days at 37 ° C., 5% CO ₂ . Cells were left untreated (DMSO control) or stimulated with various concentrations of LCL161 (1 nM, 50 nM, 100 nM or 1000 nM). For cytokine analysis, cells were stimulated with suboptimal anti-CD3 stimulation (0.005 μg / ml soluble clone UCHT1). Five days after stimulation, the supernatant was collected and analyzed for cytokines (Luminex).
As shown in FIGS. 7A-7B, LCL161 treatment resulted in an increase in the immunoreactive cytokine, IFN-cancer, and a corresponding decrease in the immunosuppressive cytokine IL-10 in vitro.
For growth analysis, cells were labeled with 5 μM carboxyfluorescein diacetate succinimidyl ester (CFSE), then stimulated and treated with 1 μg / ml soluble anti-CD3. Covalently bound CFSEs are equally divided into daughter cells, allowing identification of successful cell divisions and tracking of proliferating cells (Lyons et al., Curr Protoc Cytom. 2013; Chapter 9: Unit 9.11). .. PBMCs were stimulated for 5 days in the presence of increasing concentrations of LCL161 (or DMSO control). Five days after stimulation, cells were harvested, stained with anti-CD4, anti-CD8, anti-PD-1 or anti-CD127, followed by FACS analysis. The result from one donor is shown. Similar results were obtained with PBMCs from the other 4 donors.
As shown in FIGS. 8A-8B, LCL161 enhanced the proliferation of human CD4 + and CD8 + T cells in vitro. These results indicate the enhancement of CFSE dilution by LCL161, which is an indicator of increased lymphocyte proliferation in the presence of LCL161.

図９は、単球、ナイーブ、記憶および活性化Ｔキラー細胞ならびに記憶Ｔヘルパー細胞を含む、数細胞型における数ノードでのＴＩＭ－３発現増加を示す。これは、ＬＣＬ１６１介在免疫チェックポイントＴＩＭ－３誘導の直接の証拠である。これは、少なくとも一部、癌治療において、ＬＣＬ１６１と免疫チェックポイントモジュレーター、例えば、抗ＴＩＭ－３抗体を組み合わせる、科学的根拠を提供する。 Example 3: Effect of LCL161 on immune checkpoint regulation This example evaluates the effect of LCL161 on immune checkpoint regulation in vitro.
PBMCs were isolated from healthy donors using BD CPT ^TM vacutainer tubes. 1 million cells / mL were cultured in RPMI + 10% FBS ± 100 ng / mL anti-CD3 antibody ± DMSO or 100 nM LCL161 for 4 days. Cells were harvested, washed and stained with a set of metal conjugate antibodies listed in Table 2 below for analysis by CyTOF mass cytometry. Data was visualized by SPADE using Cytobank webware. SPADE and its use are disclosed, for example, in Peng et al., Nature Biotechnology, 29, 886-891 (2011); Sean et al, Science, 332 (6030): 687-696 (2011).

FIG. 9 shows increased TIM-3 expression at several nodes in a number of cell types, including monocytes, naive, memory and activated T killer cells as well as memory T helper cells. This is direct evidence of LCL161-mediated immune checkpoint TIM-3 induction. This provides, at least in part, the scientific basis for combining LCL161 with an immune checkpoint modulator, eg, an anti-TIM-3 antibody, in the treatment of cancer.

Example 4: Effect of LCL161 / anti-PD-1 combination on immune regulation This example shows the effect of LCL161 / anti-PD-1 combination on immune checkpoint regulation in vivo.
1 × 10 ⁶ MC38 mouse colon cancer cells / mice were implanted in C57Bl / 6 mice and randomized based on tumor measurements on day 5. Mice received LCL161 (50 mg / kg, po), anti-mouse PD-1 (10 mg / kg, iv) or both on a randomized day. In the control group, mice were dosed with vehicle (p.o.) and isotypes (mIgG1, 10 mg / kg, i.v.). Seven days after treatment, animals were sacrificed and tumors were harvested for molecular analysis.
Total RNA was extracted from the sample for genomic expression analysis. mRNA expression was analyzed on a special panel of approximately 1050 genes on the Nanostring Platform (NanoString Technologies).
The genetic signature was derived from mRNA sequencing data, which is available as part of The Cancer Genome Atlas (TCGA) and represents another 27 manifestations. For each sign, 5,000 genes were clustered into a set with a very high correlation between the samples. Clustering was performed using the gene-gene Pearson correlation matrix affinity propagation algorithm (Frey and Dueck (2007) Science 315: 972-976). The 5,000 genes clustered in each symptom consisted of 1,000 cell lineage markers and genes associated with immune processes, as well as a clustered set of 4,000 of the most diversely expressed genes in the symptom.

Clusters were annotated for identification of co-expressing genes representing specific cell types or immune processes. Annotations include mean log expression levels by immune cell type (using Immgen consortium expression data, immgen.org), mean log expression levels by normal tissue type (using GTEx data, www.gtexportal.org), and gene sets using the MSigDB collection. Concentration (calculated as Fisher's direct test p-value, testing the null hypothesis of random duplication between the cluster gene set and the MSigDB gene set) was included. Based on these annotations, clusters that were not enriched for genes involved in the immune process were excluded.
Genetic characteristics were produced by pooling clusters from all signs and identifying them as consistent annotations (eg, enriched expression in common cell type or common MSigDB pathway enrichment). Genes from these pooled clusters were then evaluated for correlation by sign. Only genes whose high level of correlation was maintained over 80% (22/27) of the manifestations were included in the final signature.
Nanostring gene signature analysis shows that combined treatment with LCL161 and anti-PD-1 increased expression properties associated with T cell, dendritic cell, macrophage and chemokine expression (FIGS. 10A-10D). The signature score in combination is higher than in each monotherapy. These data indicate that the LCL161 / anti-PD-1 combination is immunostimulatory and that the combination of LCL161 and immune checkpoint therapy further enhances antitumor immunity.

要約：
インビトロ作用機序のデータは、ＬＣＬ１６１の免疫刺激的役割を支持する。ＣｙＴＯＦによる包括的免疫プロファイリングは、免疫チェックポイント(ＴＩＭ－３)とＬＣＬ１６１の間の関連を示す。さらに、インビボ実験は、広い免疫刺激および抗腫瘍効力におけるＬＣＬ１６１とＰＤ－１の相乗的効果を示す。まとめて、実施例２～５に示すデータは、癌におけるＬＣＬ１６１と免疫チェックポイント治療の組み合わせ利益を示す。 Example 5: Efficacy of LCL161 / anti-PD-1 combination This example evaluated the efficacy of the LCL161 / anti-PD-1 combination in vivo.
C57Bl / 6 mice were implanted with 1 × 10 ⁶ MC38 cells / mouse and randomized on day 4 based on tumor measurements. The vehicle and LCL161 were given orally twice daily, weekly. Isotypes and anti-mouse PD-1 were given once a week by intravenous administration. 2 Treatment schedules were tested: 1) anti-mouse PD-1 administered 3 days after LCL161 administration; or 2) LCL161 and anti-mouse PD-1 co-administered. The test design is summarized below.
Tumor size and body weight were collected and recorded twice a week. As shown in FIGS. 11A-11B, the LCL161 / anti-PD-1 combination showed antitumor efficacy.

wrap up:
Data on in vitro mechanism of action support the immunostimulatory role of LCL161. Comprehensive immune profiling by CyTOF shows the association between immune checkpoints (TIM-3) and LCL161. In addition, in vivo experiments show the synergistic effect of LCL161 and PD-1 on broad immune stimulation and antitumor efficacy. Collectively, the data shown in Examples 2-5 show the combined benefits of LCL161 and immune checkpoint treatment in cancer.

Example 6: Dose escalation and expansion trial of LDK (seritinib) and nivolumab combination The efficacy and safety of ceritinib (LDK378) and nivolumab combination can be evaluated in open-label, multicenter dose escalation and expansion trials. In addition to safety and efficacy, the tolerability and PK / PD of the combination of ceritinib and nivolumab for the treatment of patients with metastasis, ALK-positive non-small cell lung cancer (NSCLC) can also be evaluated. The trial can be initiated from the screening phase 28 days (including 28 days) prior to the first dose of the investigational drug to assess eligibility. The treatment phase may start on the first day of the first cycle. The cycle is 28 days long.
Treatment with ceritinib and nivolumab may continue, for example, until the patient experiences unacceptable toxicity that prevents further treatment and / or disease progression.
In the case of solitary brain progression or other local progression, the patient may receive additional symptomatic radiation therapy.
The trial may include a dose escalation phase and a dose expansion phase.

1. Dose escalation phase The dose escalation phase of the study is oral administration of ceritinib with daily low-fat diet and intravenous administration every 2 weeks (Q2W) based on dose-controlled toxicity (DLT) using the Bayes Logistic Retraction Model (BLRM). The maximum tolerated dose (MTD) / recommended dose for expansion (RDE) of the combination of internal nivolumab administration can be evaluated. For example, 12 patients are enrolled in this phase of the trial. The initial dose level of ceritinib is 450 mg daily and nivolumab is administered at a dose of 3 mg / kg Q2W. The provisional dose levels are:
-[-1 dose cohort] ceritinib 300 mg + nivolumab (3 mg / kg)
-[First dose cohort] Ceritinib 450 mg + nivolumab (3 mg / kg)
-[Second dose cohort] Ceritinib 600 mg + nivolumab (3 mg / kg)
MTD is the highest dose of both drugs predicted not to cause DLT in more than 35% of treated patients in the first 6 weeks of treatment. The final recommended MTD / RDE for combination ceritinib and nivolumab is based on recommendations from BLRM and an overall assessment of safety, taking into account tolerability and pharmacokinetic data from subsequent cycles at the test dose. If the combined ceritinib and nivolumab MTDs are not established after evaluation of all planned dose levels, including target doses ceritinib (600 mg with a low-fat diet) and nivolumab (3 mg / kg), then RDE, all available safety. Determined after evaluation of sex, PK and efficacy data.

2. Once the MTD of the dose expansion phase combination has been identified and / or the RDE has been determined, additional patients will be evaluated in the expansion phase of the trial at the RDE combination dose. For example, 60 patients are enrolled in the expanded phase of the trial. The expanded phase assesses the safety and preliminary efficacy of the combination of ceritinib and nivolumab in RDE and consists of 2 arms (about 30 patients in each arm):
-Arm 1: ALK inhibitor treatment (previous treatment with any ALK inhibitor other than ceritinib is acceptable)
-Arm 2: Data cutoff for ALK inhibitor naive primary clinical trial reporting may occur if all patients in the extended phase complete at least 6 cycles (24 weeks) of treatment or withdraw early.

Example 7: Effect of LDK378 and Nivolumab Combination in Humans Eight patients were enrolled in the first dose cohort in the trial outlined in Example 6 immediately prior, with data from only patients with a valid tumor assessment below. be. A partial response was observed in this patient. A second evaluation is necessary to fully confirm this response.
The patient evaluated was a 64-year-old Caucasian male diagnosed with stage IV NSCLC. Affected areas include lungs, adrenal glands and abdominal lymph nodes. The patient had previously received one cisplatin and pemetrexed chemotherapy regimen and achieved a partial response. Further medical conditions include adrenal dysfunction, mitral valve prolapse, hypercholesterolemia and urolithiasis.
Patients started with a combination of LDK378 450 mg QD (oral) and nivolumab 3 mg / kg (intravenous) every 2 weeks given with a low-fat diet. After 29 days of the first dose of the study drug (LDK378 + nivolumab combination), the patient showed fever, abdominal pain, nausea and vomiting. Abdominal ultrasonography was negative, but abdominal computer tomography (CT) showed acute pancreatitis. In addition, there was an increase in lipase, amylase, ALT, AST, bilirubin, ALP and GGT. The patient was hospitalized and treatment with the investigational drug LDK378 was temporarily discontinued. Treatment with intravenous solution, paracetamol, Contramal (tramadol hydrochloride) and Litican (alizapride) was administered. The next day, the patient's test results improved and the patient's condition improved; there were no complaints of pain, fever, nausea and vomiting. All supportive medications were discontinued and the patient was discharged.
Subsequent assessments at the clinic showed no complaints (no fever, vomiting, nausea or abdominal pain). After the patient was discharged, the patient did not use analgesics or antiemetics. Blood tests showed that:
Lipase and amylase Within normal range, Grade 1: Bilirubin, AST and ALT Grade 2: Alkaline phosphatase Grade 3: GGT
One day after the examination at the clinic, the dose of LDK378 was reduced by 300 mg every day and resumed. Nivolumab treatment was resumed about 1 week later.
The patient vomited but had no nausea or abdominal pain. There was no fever except once there was a fever of 38 ° C. The patient had no physical complaints.
Laboratory values at the time of resumption of nivolumab: AST: 120 U / L, ALT: 139 U / L, total bilirubin 33 Umol / L, alkaline phosphatase 551 U / L. Amylase and lipase were normal.
LDK378 was discontinued and resumed at the 300 mg dose.

Tumor assessment:
CT scans during initial tumor assessment showed a 62.9% reduction in overall target lesions in the right adrenal and abdominal lymph nodes from baseline CT scans. The lower left lobe of the lung also had a non-target lesion, which was also evaluated as present.

Example 8: Phase II, multicenter, open-label clinical trial of a combination of EGF816 and nivolumab in an adult patient with EGFR mutant non-small cell lung cancer The currently approved EGFR TKI is effective against the activated EGFR mutant NSCLC. However, almost all patients develop tolerance. Utilizing the immune system to treat patients with non-small cell lung cancer (NSCLC) is a novel and bold novel treatment approach.
Simultaneous treatment with immune checkpoint inhibitors along with targeted therapy is considered safe and is expected to result in a durable and sustained response. Nivolumab is combined with the third generation EGFR TKI, EGF816, in EGFR T790MNSCLC patients who have acquired resistance to EGFR TKI treatment. The combination of nivolumab and the EGFR inhibitor, EGF816, is persistent clinical by stimulating the host immune system and blocking EGFR T790M in NSCLC patients whose tumors are resistant to EGFR TKI treatment by acquiring T790M mutations. It is expected to provide benefits.
This trial is a combination of EGF816 and nivolumab in adult patients with EGFR mutant non-small cell lung cancer, eg, patients with NSCLC advanced with standard treatment (ie, erlotinib or gefitinib against the EGFR variant NSCLC), Phase II, Multicenter, open-label clinical trial.
A dose example of EGF816 is 150 mg qd with continuous daily administration of EGF816 (capsule formulation). Various EGF 816 doses may also be used. EGF816 is administered prior to nivolumab. A minimum of 1 hour should be allowed between the administration of EGF816 and the administration of EGF816.
The dose and schedule for nivolumab is 3 mg / kg every 2 weeks. This dose and schedule selection is based on the results of safety, efficacy and exposure response analysis obtained from the trial. This dose and schedule of nivolumab is safely combined with other EGFR inhibitors at enrolled doses (eg, erlotinib) as well as other standard of care treatments.
This is a Phase II, multicenter, open-label clinical trial of patients with advanced NSCLC.
Patients are assigned based on EGFR status, eg, EGFR-T790MNSCLC.
Suitable patients are patients with advanced, relapsed or metastatic / unresectable EGFR T790MNSCLC who are progressing with standard of care (ie, erlotinib, gefitinib or other approved EGFR TKI).
The EGFR mutation state can be determined by tests available in the art, such as the QIAGEN therascreen® EGFR test. Therascreen EGFR RGQ PCR Kit is an FDA-approved qualitative real-time PCR assay for the detection of specific mutations in EGFR oncogenes. Evidence of EGFR mutations is obtained from existing local data and tumor sample tests. The EGFR mutation status can be determined from any available tumor tissue.

The patient is treated as follows.
EGF816 is given before nivolumab + nivolumab cycle is defined as 28 days.
At least 6 patients in each group constitute a safety monitoring cohort for that group.
For each cohort, patients are treated with nivolumab 3 mg / kg and 150 mg qd EGF816 (once daily) every two weeks.
As part of the safety monitoring cohort, steady-state PK profiles of EGF816 are collected on cycles 1, 15; and nivolumab trough samples are collected on cycles 1, 15.
The treatment period begins on the first and first days of cycle. The study procedure is administered during the 28-day cycle. Patients continue until unacceptable toxicity, disease progression, discontinuation of treatment or withdrawal of consent as directed by the investigator.
The order of drug administration for patients enrolled in Phase II trials treated with EGF816 and nivolumab is shown in FIG.

Incorporation by Citation All publications, patents and accession numbers mentioned herein are in their entirety as described herein by their individual publications or patents, specifically and individually by citation. Is included herein by reference.

Equivalents Although specific embodiments of the invention have been studied, the specification is descriptive and not restrictive. Many variations of the invention will be apparent to those skilled in the art who have read the specification and the accompanying claims. The complete scope of the invention, along with such variations, should be determined in light of the claims and specification with the full scope of equality.

Equivalents Although specific embodiments of the invention have been studied, the specification is descriptive and not restrictive. Many variations of the invention will be apparent to those skilled in the art who have read the specification and the accompanying claims. The complete scope of the invention, along with such variations, should be determined in light of the claims and specification with the full scope of equality.
Furthermore, the present invention includes the following aspects.
1. A combination drug containing an immunomodulatory agent and a second therapeutic agent used to treat cancer in a subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Activators of co-stimulatory molecules are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent provides 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6). Selected from one or more of histon deacetylase (HDAC) inhibitors; 7) Janus kinase inhibitors; or 8) FGF receptor inhibitors.
Combination agent.
2. A combination drug containing an immunomodulatory agent and a second therapeutic agent used to treat cancer in a subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Activators of co-stimulatory molecules are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or
8) 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide
A combination agent selected from one or more of.
3. A method of treating cancer in a subject, including administration of an immunomodulatory agent and a second therapeutic agent to the subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Activators of co-stimulatory molecules are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent provides 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6). Selected from one or more of histon deacetylase (HDAC) inhibitors; 7) Janus kinase inhibitors; or 8) FGF receptor inhibitors.
A method of treating cancer thereby.
4. A method of treating cancer in a subject, including administration of an immunomodulatory agent and a second therapeutic agent to the subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Activators of co-stimulatory molecules are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent is:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or
8) 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide
Selected from 1 or more of
A method of treating cancer thereby.
5. A method of reducing the growth, survival or viability of cancer cells, or all of them, including contacting the cells with an immunomodulatory agent and a second therapeutic agent.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Here, the agonists of the costimulatory molecule are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR. , HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or selected from one or more agonists of the CD83 ligand; and
(ii) The second therapeutic agent provides 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6). Selected from one or more of histon deacetylase (HDAC) inhibitors; 7) Janus kinase inhibitors; or 8) FGF receptor inhibitors.
A method thereby reducing the growth, survival or viability of cancer cells or all of them.
6. The inhibitor of the immune checkpoint molecule is selected from one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM or any combination thereof. The use according to Item 1 or 2 or the method according to any one of Items 3 to 5.
7. Agonists of co-stimulatory molecules are OX40, ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands. Item 5. The use according to any one of Items 1 to 2 or 6, or the method according to any one of Items 3 to 6, selected from one or more agonists of.
8. Item 8. The description of any of Items 1-2 or 6-7, wherein the immunomodulatory agent and the second therapeutic agent are administered together as a single composition or separately as two or more different compositions or dosage forms. Or the method according to any one of Items 3 to 7.
9. Use according to any one of Items 1-2 or 6-8, wherein the combination of immunomodulatory agent and the second agent is administered or contacted simultaneously or before or after the second agent. The method described in any of.
10. The use according to any one of Items 1-2 or 6-9, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand or antibody or antigen-binding fragment thereof that binds to the immune checkpoint molecule. The method described in any of.
11. The use or method of Item 10, wherein the antibody or antigen binding fragment comprises a constant region from human IgG1 or IgG4 or a modified form thereof.
12. The modified constant region is mutated to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function or complement function, item 11. Use or method.
13. The antibody molecule is a bispecific or multispecific antibody molecule having first binding specificity for PD-1 or PD-L1 and second binding specificity for TIM-3, LAG-3 or PD-L2. , Item 10. The use or method according to Item 10.
14. The use according to any one of Items 1-2 or 6-13 or the method according to any one of Items 3-13, wherein the immunomodulator is an anti-PD-1 antibody selected from nivolumab, pembrolizumab or pidirizumab. ..
15. Item 6. The immunomodulator is any of Items 1-2 or 6-13, wherein the immunomodulator is an anti-PD-L1 antibody selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105. Or the method according to any one of Items 3 to 13.
16. The use according to any one of Items 1-2 or 6-13 or the method according to any one of Items 3-13, wherein the immunomodulator is an anti-LAG-3 antibody molecule.
17. The use or method according to Item 16, wherein the anti-LAG-3 antibody molecule is BMS-986016.
18. Anti-PD-1 antibody in which the immunomodulator comprises the heavy chain amino acid sequence of SEQ ID NO: 2 and the light chain amino acid sequence of SEQ ID NO: 3; or the heavy chain amino acid sequence of SEQ ID NO: 4 and the light chain amino acid sequence of SEQ ID NO: 5. The use according to any one of Items 1 to 2 or 6 to 13, or the method according to any one of Items 3 to 13.
19. The immunomodulatory agent is an anti-PD-L1 antibody comprising the heavy chain variable amino acid sequence of SEQ ID NO: 6 and the light chain variable amino acid sequence of SEQ ID NO: 7, according to any one of Items 1-2 or 6-13. Use or the method according to any one of Items 3 to 13.
20. The use according to any one of Items 1-2 or 6-13 or the method according to any one of Items 3-13, wherein the immunomodulator is a TIM-3 inhibitor.
21. The use or method of Item 20, wherein the TIM-3 inhibitor is an antibody molecule against TIM-3.
22. The use according to any one of Items 1-2 or 6-21, wherein the cancer is a solid or soft tissue tumor selected from hematological, leukemia, lymphoma or myeloma or a metastatic lesion of any of the above cancers. Item 2. The method according to any one of Items 3 to 21.
23. Cancer is lung, breast, ovary, lymphatic system, digestive organs (eg colon), anus, genital and urogenital organs (eg kidney, urinary epithelium, bladder cells, prostate), pharynx, CNS (eg brain, etc.) A solid tumor selected from nerve or glia cells), head and neck, skin (eg, melanoma), pancreas, colon, rectum, renal cell carcinoma, liver, lung, non-small cell lung cancer, small intestine or esophagus, item. The use according to any one of 1-2 or 6-21 or the method according to any one of Items 3-21.
24. Use according to any one of Items 1-2 or 6-21, or any of Items 3-21, wherein the cancer is a hematological cancer selected from Hodgkin lymphoma, non-Hodgkin lymphoma, lymphocytic leukemia or bone marrow leukemia. The method described.
25. The use according to any one of Items 1-2 or 6-21 or the method according to any one of Items 3-21, wherein the cancer is selected from the cancers disclosed in Table 1.
26. The use according to any one of Items 1-2 or 6-25 or the method according to any one of Items 3-25, wherein the subject is a human (eg, a patient with or at risk of having cancer).
27. Immunomodulators at doses of about 1-30 mg / kg, eg, about 5-25 mg / kg, about 10-20 mg / kg, about 1-5 mg / kg or about 3 mg / kg, eg, 1 weekly. Item 6. The use according to any one of Items 1-2 or 6-26, which is an anti-PD-1 antibody molecule administered by injection (eg, subcutaneously or intravenously) once every 2 to 2 weeks, 3 weeks or 4 weeks. Alternatively, the method according to any one of Items 3 to 26.
28. The use or method of Item 27, wherein the anti-PD-1 antibody molecule is administered biweekly at a dose of about 1-20 mg / kg.
29. Anti-PD-1 antibody molecule, eg nivolumab, is administered intravenously every 2 weeks at a dose of about 1 mg / kg to 3 mg / kg, eg, about 1 mg / kg, 2 mg / kg or 3 mg / kg. , Item 26.
30. The use or method of item 26, wherein the anti-PD-1 antibody molecule, eg nivolumab, is administered intravenously at a dose of about 2 mg / kg at 3-week intervals.
31. The use according to any one of Items 1-2 or 6-30 or any of Items 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an IAP inhibitor. Method.
32. To treat immunomodulatory agents for the cancers or disorders listed in Table 1, such as solid tumors, such as breast cancer, colon cancer or pancreatic cancer; or hematopoietic tumors, such as multiple myeloma or hematopoietic disorders. , Nivolumab, Pembrolizumab or MSB0010718C used in combination with LCL161, where LCL161 is (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4) -The use or item according to any one of Items 1-2 or 6-30, which is fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide. The method according to any one of 3 to 30.
33. LCL161 is about 10 to 3000 mg, for example, about 20 to 2400 mg, about 50 to 1800 mg, about 100 to 1500 mg, about 200 to 1200 mg, about 300 to 900 mg, for example, about 600 mg, about 900 mg, about 1200 mg, about 1500 mg. 32. The use or method according to Item 32, which is administered at an oral dose of about 1800 mg, about 2100 mg or about 2400 mg. In some embodiments, LCL161 is administered once a week or once every two weeks.
34. The use according to any one of Items 1-2 or 6-30 or any of Items 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a TOR kinase inhibitor. the method of.
35. Immunomodulators are cancers or disorders listed in Table 1, such as solid tumors, such as sarcoma, lung cancer (eg, non-small cell lung cancer (NSCLC)) (eg, squamous epithelium and / or non-squamous epithelial histology). NSCLC)), melanoma (eg, advanced melanoma), gastrointestinal / gastrointestinal cancer, gastric cancer, neurological cancer, prostate cancer, bladder cancer, breast cancer; or hematopoietic tumors, such as lymphoma or leukemia. Nivormab, Pembrolizumab or MSB0010718C used in combination with Rad-001, where Rad-001 is ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E,). 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2-[(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1- Methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo [30.3.1.04,9] hexatria contour 16,24,26,28-tetraen-2,3,10,14,20-pentaone), according to any one of Items 1-2 or 6-30 or any of Items 3-30. the method of.
36. The use according to any one of Items 1-2 or 6-30 or any of Items 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an HDM2 ligase inhibitor. the method of.
37. The immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with CGM097 to treat the cancers or disorders listed in Table 1, eg, CGM097 is (S) -1. -(4-Chlorophenyl) -7-isopropoxy-6-methoxy-2-(4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl) -trans-cyclohexylmethyl] -amino } Phenyl) -1,4-dihydro-2H-isoquinoline-3-one, the use according to any one of Items 1-2 or 6-30 or the method according to any one of Items 3-30.
38. The use according to any one of Items 1-2 or 6-30 or any of Items 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a PIM kinase inhibitor. the method of.
39. Immunomodulators are used in combination with LGH447 to treat the cancers or disorders listed in Table 1, such as hematopoietic tumors, such as multiple myeloma, myelodysplastic syndrome, myelodysplastic or non-Hodgkin's lymphoma. Nivolumab, Pembrolizumab or MSB0010718C, where LGH447 is N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridine-3-yl) -6- (2, 6-Difluorophenyl) -3-fluoropicolinamide, the use according to any one of Items 1-2 or 6-30 or the method according to any one of Items 3-30.
40. The use according to any one of Items 1-2 or 6-30 or any of Items 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a HER3 kinase inhibitor. the method of.
41. Immunomodulators are combined with LJM716 to treat the cancers or disorders listed in Table 1, such as solid tumors such as gastric cancer, esophageal cancer, breast cancer, head and neck cancer, gastric cancer or gastrointestinal / gastrointestinal cancer treatment. Nivolumab, Pembrolizumab or MSB0010718C used in, where LJM716 is an anti-HER3 monoclonal antibody or an anti-HER3 monoclonal antibody comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as described in US 8,735,551. The use according to any one of Items 1-2 or 6-30, which is an antigen-binding fragment, or the method according to any one of Items 3-30.
42. The use according to any one of Items 1-2 or 6-30 or any of Items 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an HDAC inhibitor. Method.
43. Immunomodulators are cancers or disorders listed in Table 1, such as solid tumors such as bone cancer, small cell lung cancer, respiratory / chest cancer, prostate cancer, non-small cell lung cancer (NSCLC), neurogenic. Cancer, gastric cancer, melanoma, breast cancer, pancreatic cancer, colorectal cancer, kidney cancer or head and neck cancer or liver cancer; or hematopoietic tumors such as multiple myeloma, hematopoietic disorders, myelodystrophy syndrome, lymphoma (eg) Nivormab, Pembrolizumab or MSB0010718C used in combination with LBH589 to treat non-hodgkin lymphoma) or leukemia (eg, myeloid leukemia), where LBH589 is (E) -N-hydroxy-3- (4-). ((2- (2-Methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) The use according to any one of Items 1-2 or 6-30 or Item 3-30. The method described in either.
44. The use according to any one of Items 1-2 or 6-30 or any of Items 23-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a Janus kinase inhibitor. the method of.
45. Immunomodulators are cancers or disorders listed in Table 1, such as solid tumors such as prostate cancer, lung cancer, leukemia, pancreatic cancer, colorectal cancer; or hematopoietic tumors such as multiple myeloma, lymphoma. Nivormab, Pembrolizumab or MSB0010718C used in combination with INC42 to treat (eg, non-Hodgkin's lymphoma) or leukemia (eg, myeloid leukemia, lymphocytic leukemia), where INC424 is (3R) -3-. Cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanenitrile, any of items 1-2 or 6-30. The use according to item 3 or the method according to any one of Items 3 to 30.
46. The use or method of Item 45, wherein the cancer has or is identified as having a JAK mutation, eg, a JAK2 V617F mutation.
47. The use according to any one of Items 1-2 or 6-30 or any of Items 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an FGF receptor inhibitor. the method of.
48. The immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with BUW078 to treat the cancers listed in Table 1, such as solid tumors such as gastrointestinal / gastrointestinal cancers; or hematological cancers. Where BUW078 is 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxalin-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide, The use according to any one of Items 1 to 2 or 6 to 30 or the method according to any one of Items 3 to 30.
49. A combination of an anti-PD-1 antibody or anti-TIM-3 antibody and a second therapeutic agent used to treat cancer in a subject.
(i) PD-1 inhibitors are selected from nivolumab, pembrolizumab or pidirizumab;
(ii) The second therapeutic agent is:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or
8) 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide
A combination agent selected from one or more of.
50. A method comprising administering to a subject an anti-PD-1 antibody or an anti-TIM-3 antibody and a second therapeutic agent to treat the cancer in the subject.
(i) PD-1 inhibitors are selected from nivolumab, pembrolizumab or pidirizumab; and
(ii) The second therapeutic agent is:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or
8) 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide
Selected from 1 or more of
A method of treating cancer thereby.
51. Immunomodulators (eg, one or more activators of costimulatory molecules or inhibitors of immune checkpoint molecules) and second therapeutic agents, eg, 1) IAP inhibitors; 2) TOR kinase inhibitors provided in Table 1. Agents; 3) HDM2 ligase inhibitors; 4) PIM kinase inhibitors; 5) HER3 kinase inhibitors; 6) Histon deacetylase (HDAC) inhibitors; 7) Janus kinase inhibitors; or 8) FGF receptor inhibitors A composition (eg, one or more compositions or dosage forms) comprising a second therapeutic agent selected from one or more of the above.

Claims (51)

A combination containing an immunomodulator and a second-line therapeutic agent used to treat cancer in a subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Co-stimulatory molecule activators are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent provides 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) Selected from one or more of histon deacetylase (HDAC) inhibitors; 7) yanus kinase inhibitors; or 8) FGF receptor inhibitors.
Combination agent. A combination containing an immunomodulator and a second-line therapeutic agent used to treat cancer in a subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Co-stimulatory molecule activators are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent is 1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-Hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or 8) A combination selected from one or more of 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxalin-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide. Agent. A method of treating cancer in a subject, including administration of an immunomodulatory agent and a second therapeutic agent to the subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a costimulatory molecule or a combination thereof, wherein the inhibitor of the immune checkpoint molecule is PD-1, PD-L1, PD-L2, Selected from one or more inhibitors of CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta.
Activators of co-stimulatory molecules are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent provides 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) Selected from one or more of histon deacetylase (HDAC) inhibitors; 7) yanus kinase inhibitors; or 8) FGF receptor inhibitors.
A method of treating cancer thereby. A method of treating cancer in a subject, including administration of an immunomodulatory agent and a second therapeutic agent to the subject.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a costimulatory molecule or a combination thereof, wherein the inhibitor of the immune checkpoint molecule is PD-1, PD-L1, PD-L2, Selected from one or more inhibitors of CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta.
Activators of co-stimulatory molecules are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, Selected from one or more agonists of CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands; and
(ii) The second therapeutic agent is:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-Hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or 8) It is selected from one or more of 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxalin-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide.
A method of treating cancer thereby. A method of reducing the growth, survival or viability of cancer cells, or all of them, comprising contacting the cells with an immunomodulator and a second therapeutic agent.
(i) The immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a co-stimulatory molecule or a combination thereof.
Here, the inhibitors of the immune checkpoint molecule are PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR. Selected from one or more inhibitors of beta,
Here, the agonists of the costimulatory molecule are OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR. , HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or selected from one or more agonists of the CD83 ligand; and
(ii) The second therapeutic agent provides 1) IAP inhibitor; 2) TOR kinase inhibitor; 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) Selected from one or more of histon deacetylase (HDAC) inhibitors; 7) yanus kinase inhibitors; or 8) FGF receptor inhibitors.
A method thereby reducing the growth, survival or viability of cancer cells or all of them. Claimed that the inhibitor of the immune checkpoint molecule is selected from one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM or any combination thereof. The use according to 1 or 2 or the method according to any one of claims 3-5. Agonists of co-stimulatory molecules are one of OX40, ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand. The use according to any one of claims 1 to 2 or 6 or the method according to any one of claims 3 to 6, selected from the above agonists. The invention according to any one of claims 1 to 2 or 6 to 7, wherein the immunomodulator and the second therapeutic agent are administered together as a single composition or separately as two or more different compositions or dosage forms. Use or the method according to any one of claims 3-7. The use or claim 3-8 according to any one of claims 1-2 or 6-8, wherein the combination of the immunomodulator and the second agent is administered or contacted simultaneously or before or after the second agent. The method described in any of. The use or claim 8-9 according to any one of claims 1-2 or 6-9, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand or antibody or antigen-binding fragment thereof that binds to the immune checkpoint molecule. The method described in any of. 10. The use or method of claim 10, wherein the antibody or antigen binding fragment comprises a constant region from human IgG1 or IgG4 or a modified form thereof. 22. The use of claim 11, wherein the modified constant region is mutated to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function or complement function. Or how. Claimed that the antibody molecule is a bispecific or multispecific antibody molecule having a first binding specificity for PD-1 or PD-L1 and a second binding specificity for TIM-3, LAG-3 or PD-L2. Item 10. The use or method according to Item 10. The use according to any one of claims 1-2 or 6-13, or the method according to any one of claims 3-13, wherein the immunomodulator is an anti-PD-1 antibody selected from nivolumab, pembrolizumab or pidirizumab. .. 13. Use or the method of any of claims 3-13. The use according to any one of claims 1-2 or 6-13, or the method according to any one of claims 3-13, wherein the immunomodulator is an anti-LAG-3 antibody molecule. 16. The use or method of claim 16, wherein the anti-LAG-3 antibody molecule is BMS-986016. The immunomodulator is an anti-PD-1 antibody comprising the heavy chain amino acid sequence of SEQ ID NO: 2 and the light chain amino acid sequence of SEQ ID NO: 3; or the heavy chain amino acid sequence of SEQ ID NO: 4 and the light chain amino acid sequence of SEQ ID NO: 5. , The use according to any one of claims 1-2 or 6-13 or the method according to any one of claims 3-13. The use according to any one of claims 1-2 or 6-13, wherein the immunomodulator is an anti-PD-L1 antibody comprising the heavy chain variable amino acid sequence of SEQ ID NO: 6 and the light chain variable amino acid sequence of SEQ ID NO: 7. Alternatively, the method according to any one of claims 3 to 13. The use according to any one of claims 1-2 or 6-13 or the method according to any one of claims 3-13, wherein the immunomodulator is a TIM-3 inhibitor. 20. The use or method of claim 20, wherein the TIM-3 inhibitor is an antibody molecule against TIM-3. The use or claim according to any one of claims 1-2 or 6-21, wherein the cancer is a solid tumor or soft tissue tumor selected from hematologic cancer, leukemia, lymphoma or myeloma or a metastatic lesion of any of said cancers. Item 2. The method according to any one of Items 3 to 21. Cancer can be lung, breast, ovary, lymphatic system, digestive system (eg colon), anus, genital and urogenital (eg kidney, urinary epithelium, bladder cells, prostate), pharynx, CNS (eg brain, nerve or 1 The use according to any one of 2 or 6-21 or the method according to any one of claims 3-21. The use according to any one of claims 1-2 or 6-21, or any of claims 3-21, wherein the cancer is a hematological cancer selected from Hodgkin lymphoma, non-Hodgkin lymphoma, lymphocytic leukemia or bone marrow leukemia. The method described. The use according to any one of claims 1-2 or 6-21 or the method according to any one of claims 3-21, wherein the cancer is selected from the cancers disclosed in Table 1. The use according to any one of claims 1-2 or 6-25 or the method according to any one of claims 3-25, wherein the subject is a human (eg, a patient with or at risk of having cancer). Immunomodulators are available in doses of about 1-30 mg / kg, eg, about 5-25 mg / kg, about 10-20 mg / kg, about 1-5 mg / kg or about 3 mg / kg, eg, once a week. The use according to any one of claims 1-2 or 6-26, which is an anti-PD-1 antibody molecule administered by injection (eg, subcutaneously or intravenously) once every 2 weeks, 3 weeks or 4 weeks. The method according to any one of claims 3 to 26. 27. The use or method of claim 27, wherein the anti-PD-1 antibody molecule is administered biweekly at a dose of about 1-20 mg / kg. An anti-PD-1 antibody molecule, such as nivolumab, is administered intravenously every two weeks at a dose of about 1 mg / kg to 3 mg / kg, such as about 1 mg / kg, 2 mg / kg or 3 mg / kg. Item 26. The use or method according to item 26. 26. The use or method of claim 26, wherein the anti-PD-1 antibody molecule, eg, nivolumab, is administered intravenously at a dose of about 2 mg / kg at 3-week intervals. The use according to any one of claims 1-2 or 6-30, or any of claims 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an IAP inhibitor. Method. LCL161 for immunomodulatory agents to treat cancers or disorders listed in Table 1, such as solid tumors, such as breast cancer, colon cancer or pancreatic cancer; or hematopoietic tumors, such as multiple myeloma or hematopoietic disorders. Nivolumab, Pembrolizumab or MSB0010718C used in combination with, where LCL161 is (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluoro). The use or claim according to any one of claims 1-2 or 6-30, which is benzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide. The method according to any one of 3 to 30. LCL161 is about 10 to 3000 mg, for example, about 20 to 2400 mg, about 50 to 1800 mg, about 100 to 1500 mg, about 200 to 1200 mg, about 300 to 900 mg, for example, about 600 mg, about 900 mg, about 1200 mg, about 1500 mg, about. 32. The use or method of claim 32, which is administered at an oral dose of 1800 mg, about 2100 mg or about 2400 mg. In some embodiments, LCL161 is administered once a week or once every two weeks. The use according to any one of claims 1-2 or 6-30, or any of claims 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a TOR kinase inhibitor. the method of. Immunomodulators have the cancers or disorders listed in Table 1, eg, solid tumors, eg, sarcoma, lung cancer (eg, non-small cell lung cancer (NSCLC)) (eg, squamous epithelium and / or non-squamous epithelial histology). NSCLC)), melanoma (eg, advanced melanoma), gastrointestinal / gastrointestinal cancer, gastric cancer, neurogenic cancer, prostate cancer, bladder cancer, breast cancer; or hematopoietic tumors, such as lymphoma or leukemia. Nivolumab, Pembrolizumab or MSB0010718C used in combination with Rad-001, where Rad-001 is ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E,). 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2-[(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl } -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo [30.3.1.04,9] hexatria contour-16, 24,26,28-tetraen-2,3,10,14,20-pentaone), according to any one of claims 1-2 or 6-30 or any of claims 3-30. the method of. The use according to any one of claims 1-2 or 6-30, or any of claims 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an HDM2 ligase inhibitor. the method of. The immunomodulatory agent is nivolumab, pembrolizumab or MSB0010718C used in combination with CGM097 to treat the cancers or disorders listed in Table 1, such as CGM097 (S) -1-(. 4-Chlorophenyl) -7-isopropoxy-6-methoxy-2-(4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl) -trans-cyclohexylmethyl] -amino} phenyl ) -1,4-Dihydro-2H-isoquinoline-3-one, the use according to any one of claims 1-2 or 6-30 or the method according to any one of claims 3-30. The use according to any one of claims 1-2 or 6-30, or any of claims 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a PIM kinase inhibitor. the method of. Immunomodulators are used in combination with LGH447 to treat the cancers or disorders listed in Table 1, such as hematopoietic tumors, such as multiple myeloma, myelodysplastic syndrome, myelodysplastic or non-Hodgkin's lymphoma. Nivolumab, Pembrolizumab or MSB0010718C, where LGH447 is N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridine-3-yl) -6- (2,6-yl). The use according to any one of claims 1-2 or 6-30 or the method according to any one of claims 3-30, which is difluorophenyl) -3-fluoropicolinamide. The use according to any one of claims 1-2 or 6-30, or any of claims 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a HER3 kinase inhibitor. the method of. Immunomodulators are used in combination with LJM716 to treat the cancers or disorders listed in Table 1, eg, solid tumors such as gastric cancer, esophageal cancer, breast cancer, head and neck cancer, gastric cancer or gastrointestinal / gastrointestinal cancer treatment. Nivolumab, Pembrolizumab or MSB0010718C, wherein LJM716 comprises an anti-HER3 monoclonal antibody or antigen binding thereof, comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as described in US 8,735,551. The use according to any one of claims 1-2 or 6-30 or the method according to any one of claims 3-30, which is a fragment. The use according to any one of claims 1-2 or 6-30, or any of claims 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an HDAC inhibitor. Method. Immunomodulators include cancers or disorders listed in Table 1, such as solid tumors such as bone cancer, small cell lung cancer, respiratory / chest cancer, prostate cancer, non-small cell lung cancer (NSCLC), neurological cancer, Gastric cancer, melanoma, breast cancer, pancreatic cancer, colorectal cancer, kidney cancer or head and neck cancer or liver cancer; or hematopoietic tumors such as multiple myeloma, hematopoietic disorders, myelodystrophy syndrome, lymphoma (eg non-hodgkin) Nivormab, Pembrolizumab or MSB0010718C used in combination with LBH589 to treat lymphoma) or leukemia (eg, myeloid leukemia), where LBH589 is (E) -N-hydroxy-3-(4-(((). (2- (2-Methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) The use according to any one of claims 1-2 or 6-30 or claim 3-30, which is acrylamide. The method described in either. The use according to any one of claims 1-2 or 6-30, or any of claims 23-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with a Janus kinase inhibitor. the method of. Immunomodulators are cancers or disorders listed in Table 1, such as solid tumors, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer; or hematopoietic tumors, such as multiple myeloma, lymphoma (eg, multiple myeloma, lymphoma). , Non-Hodgkin's lymphoma) or nibolumab, penbrolizumab or MSB0010718C used in combination with INC42 to treat leukemia (eg, myeloid leukemia, lymphocytic leukemia), where INC424 is (3R) -3-cyclopentyl-. 3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanenitrile, according to any one of claims 1-2 or 6-30. Use of the description or the method according to any one of claims 3 to 30. 45. The use or method of claim 45, wherein the cancer has or is identified as having or having a JAK mutation, eg, a JAK2 V617F mutation. The use according to any one of claims 1-2 or 6-30, or any of claims 3-30, wherein the immunomodulator is nivolumab, pembrolizumab or MSB0010718C used in combination with an FGF receptor inhibitor. the method of. The immunomodulatory agent is nivolumab, pembrolizumab or MSB0010718C used in combination with BUW078 to treat the cancers listed in Table 1, eg, solid tumors, eg digestive / gastrointestinal cancers; or hematologic cancers. According to the claim, BUW078 is 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxalin-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide. The use according to any one of 1-2 or 6-30 or the method according to any one of claims 3-30. A combination of an anti-PD-1 antibody or an anti-TIM-3 antibody and a second therapeutic agent used to treat cancer in a subject.
(i) PD-1 inhibitors are selected from nivolumab, pembrolizumab or pidirizumab;
(ii) The second therapeutic agent is:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-Hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or 8) A combination selected from one or more of 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxalin-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide. Agent. A method comprising administering to a subject an anti-PD-1 antibody or an anti-TIM-3 antibody and a second therapeutic agent to treat cancer in the subject.
(i) PD-1 inhibitors are selected from nivolumab, pembrolizumab or pidirizumab; and
(ii) The second therapeutic agent is:
1) (S) -N-((S) -1-cyclohexyl-2-((S) -2- (4- (4-fluorobenzoyl) thiazole-2-yl) pyrrolidine-1-yl) -2- Oxoethyl) -2- (methylamino) propanamide;
2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy-12-{(1R) -2- [(1S, 3R, 4R) -4- (2-Hydroxyethoxy) -3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl- 11,36-Dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);
3) (S) -1- (4-chlorophenyl) -7-isopropoxy-6-methoxy-2- (4- {methyl- [4- (4-methyl-3-oxo-piperazine-1-yl)-)- trans-cyclohexylmethyl] -amino} phenyl) -1,4-dihydro-2H-isoquinoline-3-one;
4) N- (4-((1R, 3S, 5S) -3-amino-5-methylcyclohexyl) pyridin-3-yl) -6- (2,6-difluorophenyl) -5-fluoropicoline amide;
5) An anti-HER3 monoclonal antibody or antigen-binding fragment thereof comprising VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as set forth in US 8,735,551;
6) (E) -N-hydroxy-3-(4-(((2- (2-methyl-1H-indole-3-yl) ethyl) amino) methyl) phenyl) acrylamide;
7) (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1-yl] propanenitrile; and / or 8) It is selected from one or more of 8- (2,6-difluoro-3,5-dimethoxy-phenyl) -quinoxalin-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl) -amide.
A method of treating cancer thereby. Immunomodulators (eg, one or more activators of costimulatory molecules or inhibitors of immune checkpoint molecules) and second therapeutic agents, eg, 1) IAP inhibitors; 2) TOR kinase inhibitors provided in Table 1, eg. 3) HDM2 ligase inhibitor; 4) PIM kinase inhibitor; 5) HER3 kinase inhibitor; 6) Histon deacetylase (HDAC) inhibitor; 7) Janus kinase inhibitor; or 8) FGF receptor inhibitor 1 A composition (eg, one or more compositions or dosage forms) comprising a second therapeutic agent selected from the above.

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